Modulation of sensory inputs and ectopic presence of Schwann cells depend upon the route and duration of nerve growth factor administration

Nerve growth factor (NGF) ameliorates deficits in models of cholinergic hypofunction. However, notable adverse effects of intracerebroventricular (ICV) infusion of NGF include weight loss, Schwann cell hyperplasia (SCH), and aberrant sensory and sympathetic sprouting. In order to maintain efficacy on the cholinergic basal forebrain (CBF) and minimize these detrimental effects, intraparenchymal NGF infusion was compared with ICV administration to assess morphological and functional measures. NGF was delivered intraparenchymally (Intra-NGF) or intracerebroventricularly (ICV-NGF) for 3 and 6 months. Hypertrophy of cholinergic nucleus basalis neurons at 3 and 6 months was not different between both routes of administration, indicating similar efficacy for the CBF. SCH surrounding the medulla was observed in both Intra- and ICV-NGF animals due to the widespread distribution of NGF from the infusion site. The thickness of SCH reached a plateau at 3 months in ICV-NGF animals, while further proliferation occurred in Intra-NGF animals. More importantly, ectopic Schwann cells and aberrant sensory and sympathetic sprouting within the medulla oblongata were found solely in ICV-NGF animals. Differential changes in sensory processing were evident by an exaggerated response to acoustic stimuli in Intra-NGF animals and a decrease in thermal pain threshold in ICV-NGF-treated animals. Intra-NGF treatment did not produce the reduction in body weight exhibited by ICV-NGF-treated rats. These results indicate that different routes of NGF administration are identically efficacious for CBF neurons, but differentially modulate behaviors and structures leading to distinct profiles of adverse effects. Thus, current trophic factor delivery methods require further refinement to abolish detrimental effects.     

Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain: response to fimbria-fornix transection

Although it is well known that magnocellular cholinergic basal forebrain neurons are trophically responsive to nerve growth factor (NGF) and contain NGF receptors (NGFr), the exact distribution of forebrain NGFr-immunoreactive neurons and the degree to which cholinergic neurons are colocalized with them have remained in question. In this study we employed a very sensitive double-labelling method and examined in the same tissue section the distribution and cellular features of NGFr-positive and choline acetyltransferase (ChAT)-immunolabelled neurons within the rat basal forebrain. Throughout this region the majority of magnocellular basal forebrain neurons were immunoreactive for both NGFr and ChAT. However, a small percentage of neurons in the ventral portion of the vertical limb of the diagonal band of Broca were immunoreactive only for NGFr, whereas a larger population of magnocellular neurons in the substantia innominata exhibited only ChAT immunoreactivity. No NGFr-immunoreactive cells were found associated with ChAT-positive neurons in the striatum, neocortex, or hippocampus, and no single-labelled NGFr-immunoreactive neurons were found outside the basal forebrain area, except for a large number of positive-labelled cells along the ventricular walls of the third ventricle. In addition to its function in maintaining the normal integrity of the basal forebrain and cholinergic, peripheral sympathetic, and neural-crest-derived sensory neurons, NGF may also have a role in the growth of these neurons after damage to the nervous system. To examine this postulate the hippocampus was denervated of its septal input and examined 8 weeks later. Two populations of neurons were found to have undergone collateral sprouting--namely, the midline magnocellular cholinergic neurons of the dorsal hippocampus and the sympathetic noradrenergic neurons of the superior cervical ganglion. Both of these neuronal populations also stained strongly for NGFr. In contrast, the small intrinsic cholinergic neurons of the hippocampus exhibited neither sprouting response nor staining for NGFr. In view of these results, we suggest that the differing sprouting responses demonstrated by these three neuronal populations may be due to their responsiveness to NGF, as indicated by the presence or absence of NGF receptors.     

Nerve growth factor increases choline acetyltransferase activity in developing basal forebrain neurons

Nerve growth factor (NGF) is a neuronotrophic protein. Its effects on developing peripheral sensory and sympathetic neurons have been extensively characterized, but it is not clear whether NGF plays a role during the development of central nervous system neurons. To address this point, we examined the effect of NGF on the activity of neurotransmitter enzymes in several brain regions. Intracerebroventricular injections of highly purified mouse NGF had a marked effect on the activity of choline acetyltransferase (ChAT), a selective marker of cholinergic neurons. NGF elicited prominent increases in ChAT activity in the basal forebrain of neonatal rats, including the septum and a region which contains neurons of the nucleus basalis and substantia innominata. NGF also increased ChAT activity in the hippocampus and neocortex, terminal regions for the fibers of basal forebrain cholinergic neurons. In analogy with the response of developing peripheral neurons, the NGF effect was shown to be selective for basal forebrain cholinergic cells and to be dose-dependent. Furthermore, septal neurons closely resembled sympathetic neurons in the time course of their response to NGF. These observations suggest that endogenous NGF does play a role in the development of basal forebrain cholinergic neurons.     

Trophic protection of motor neurons: clinical potential in motor neuron diseases

Recent advances in understanding the physiologic role of nerve growth factor (NGF), obtained both from tissue culture and efficacy studies in animals, have suggested that neurotrophic factors may have clinical potential in the treatment of neurodegenerative diseases or nerve trauma [12, 21]. First characterized as a target-derived survival factor for developing sympathetic and sensory neurons, it is now clear that NGF plays an important role in the maintenance and regeneration of mature peripheral neurons. Prompted by in vitro findings, it was established in the mid-1980's that intracerebroventricular infusions of NGF are capable of rescuing basal forebrain cholineric neurons from axotomy-induced cell death produced by fimbria-fornix lesion. Given that degeneration of cholinergic neurons is a major contributing factor in the loss of cognitive function in Alzheimer's disease, there has been a great deal of interest in exploring the therapeutic potential of NGF in this disease [16]. The highly restricted specificity of NGF for sympathetic neurons, sub-populations of neural crest-derived sensory neurons and striatal and basal forebrain cholinergic neurons has for almost two decades spurred the search for other neurotrophic factors with specificities directed to the many classes of neurons which do not respond to NGF. The biology of the recently discovered NGF-related family of neurotrophic factors, the neurotrophins and ciliary neurotrophic factor (CNTF), and their receptors, offers new prospects for the therapeutic potential of neurotrophic factors in the motor neuron diseases.     

Loss of nerve growth factor receptor-containing neurons in Alzheimer's disease: a quantitative analysis across subregions of the basal forebrain

Magnocellular neurons comprising the Ch1-Ch4 regions of the basal forebrain provide topographic cholinergic innervation to the cerebral cortex, thalamus, and basolateral nucleus of the amygdala. Most quantitative studies analyzing the status of these neurons in Alzheimer's disease (AD) have employed Nissl-stained preparations. These studies principally analyzed large neurons of a prespecified cell diameter. Since basal forebrain neurons atrophy in Alzheimer's disease, an immunocytochemical marker for these neurons would appear to be a better alternative for determining whether there is regionally specific degeneration of cholinergic neurons across subregions of the basal forebrain. Brain sections from seven AD and five aged-matched control patients were immunocytochemically stained with a monoclonal antibody raised against the receptor for nerve growth factor (NGF), a probe which has previously been demonstrated to extensively and exclusively colocalize with cholinergic basal forebrain neurons in humans (17, 25, 35). NGF receptor-immunoreactive neurons within the hippocampal projecting nuclei of the medial septum (Ch1) and vertical limb of the diagonal band (Ch2) were minimally affected in AD as compared to control cases. In contrast, the Ch4 region demonstrated a significant loss of NGF receptor-immunoreactive neurons in AD that inversely correlated (-0.786) with the duration of the disease process. All four subregions of Ch4 were affected in the AD cases with the anterolateral (76.4%), intermediate (62.1%) and posterior divisions (76.5%) demonstrating the greatest reduction in NGF receptor-immunoreactive neurons. Nissl-counterstained sections failed to reveal magnocellular neurons which were not immunoreactive for the NGF receptor, suggesting that reductions in immunocytochemically stained neurons reflects neuron loss and not the failure of viable neurons to synthesize NGF receptors. These data indicate that cholinergic basal forebrain neurons which project to the amygdala, as well as to the temporal, frontobasal, and frontodorsal cortices, are most affected in AD.     

Evidence that perihypoglossal neurons involved in vestibular-auditory and gaze control functions respond to nerve growth factor

Nerve growth factor (NGF), which has long been considered to be a trophic factor for peripheral sensory and sympathetic neurons, has been found recently to influence cholinergic neurons in the basal forebrain and neostriatum. In the present study, we provide evidence that brainstem neurons in the perihypoglossal area that relay information from the inner ear and vestibular apparatus to the cerebellum and tectum are responsive to NGF. These neurons, which are located in the nucleus prepositus hypoglossi (NPH), spinal vestibular nucleus, cochlear complex, and gigantocellular and paragigantocellular nuclei of the reticular formation, express functional receptors for NGF and up-regulate the expression of trkA receptors after injection of NGF into targets. In addition, the developmental up-regulation of NGF in the cerebellum coincides with the differentiation of the perihypoglossal nuclei. These results suggest that neurons representing the principal brain relays for auditory and vestibular pathways and perihypoglossal neurons involved in gaze coordination are a novel group of central neurons (besides cholinergic neurons in the basal forebrain and neostriatum) that respond to NGF. J. Comp. Neurol. 383:123-134, 1997. © 1997 Wiley-Liss, Inc.     

Immunolesioning: selective destruction of neurons using immunotoxin to rat NGF receptor.

192 IgG, a monoclonal antibody to the rat nerve growth factor (NGF) receptor, was disulfide-coupled to saporin, a ribosome-inactivating protein. Systemic injection of 192 IgG-saporin destroyed sympathetic postganglionic neurons and some sensory neurons. Injection of 192 IgG-saporin into the lateral ventricle destroyed cholinergic neurons of the basal forebrain. These results show that antineuronal immunotoxins are a powerful approach that may prove useful in a variety of neurobiological applications.     

Long-term reversal of cholinergic neuronal decline in aged non-human primates by lentiviral NGF gene delivery

Spontaneous atrophy of basal forebrain cholinergic neurons occurs with aging in the non-human primate brain. Short-term reversal of this atrophy has been reported following ex vivo nerve growth factor (NGF) gene delivery, but long-term effects of in vivo NGF gene delivery in the aged primate brain have not to date been examined. We tested the hypothesis that long-term lentiviral NGF intraparenchymal gene delivery would reverse age-related cholinergic decline, without induction of adverse effects previously observed following sustained intracerebroventricular growth factor protein exposure. Three aged rhesus monkeys underwent intraparenchymal lentiviral NGF gene delivery to the cholinergic basal forebrain. 1 year later, cholinergic neuronal numbers were quantified stereologically and compared to findings in four controls, non-treated aged monkeys and four young adult monkeys. Safety was assessed on several variables related to growth factor exposure. We now report that lentiviral gene delivery of NGF to the aged primate basal forebrain sustains gene expression for at least 1 year, and significantly restores cholinergic neuronal markers to levels of young monkeys. Aging resulted in a significant 17% reduction (p < 0.05) in the number of neurons labeled for the cholinergic marker p75 among basal forebrain neurons. Lentiviral NGF gene delivery induced significant (p < 0.05) and nearly complete recovery of p75-labeled neuronal numbers in aged subjects to levels observed in young monkeys. Similarly, the size of cholinergic neurons in aged monkeys was significantly reduced by 16% compared to young subjects (p < 0.05), and lentiviral NGF delivery to aged subjects induced complete recovery of neuronal size. Intraparenchymal NGF gene delivery over a one-year period did not result in systemic leakage of NGF, activation of inflammatory markers in the brain, pain, weight loss, Schwann cell migration, or formation of anti-NGF antibodies. These findings indicate that extended trophic support to neurons in the non-human primate brain reverses age-related neuronal atrophy. These findings also support the safety and feasibility of lentiviral NGF gene transfer for potential testing in human clinical trials to protect degenerating cholinergic neurons in Alzheimer's disease.     

Entorhinal lesions result in increased nerve growth factor-like growth-promoting activity in medium conditioned by hippocampal slices

Nerve growth factor (NGF) is present in high concentrations in the rat hippocampal formation where it may be involved in sympathetic sprouting following septohippocampal denervation. In addition, recent evidence suggests that some forebrain cholinergic neurons, including septohippocampal neurons, are responsive to exogenous NGF. Since septohippocampal neurons have been shown to sprout in response to entorhinal lesions both in rats and, recently, in humans, we sought to determine whether endogenous NGF-like activity increases in the rat hippocampal formation following injury to the entorhinal cortex. We found that entorhinal lesions which result in extensive denervation of the dentate granule cells, and subsequent sprouting of septohippocampal axons, do result in greater NGF-like growth-promoting activity in medium conditioned by slices of the denervated tissue when compared to medium conditioned by control tissue. These results suggest that brain NGF may be involved in injury-induced sprouting of forebrain cholinergic neurons.     

Entorhinal lesions result in increased nerved growth factor-like growth-promoting activity in medium conditioned by hippocampal slices

Nerve growth factor (NGF) is present in high concentrations in the rat hippocampal formation where it may be involved in sympathetic sprouting following septohippocampal denervation. In addition, recent evidence suggests that some forebrain cholinergic neurons, including septohippocampal neurons, are responsive to exogenous NGF. Since septohippocampal neurons have been shown to sprout in response to entorhinal lesions both in rats and, recently, in humans, we sought to determine whether endogenous NGF-like activity increases in the rat hippocampal formation following injury to the entorhinal cortex. We found that entorhinal lesions which result in extensive denervation of the dentate granule cells, and subsequent sprouting of septohippocampal axons, do result in greater NGF-like growth-promoting activity in medium conditioned by slices of the denervated tissue when compared to medium conditioned by control tissue. These results suggest that brain NGF may be involved in injury-induced sprouting of forebrain cholinergic neurons.     

Age-related loss of nerve growth factor sensitivity in rat basal forebrain neurons

Nerve growth factor (NGF) has recently been implicated as a trophic agent in the survival and maintenance of basal forebrain cholinergic neurons. To test the hypothesis that NGF may play a role in the age-related degeneration of basal forebrain neurons and decline of cerebral cholinergic function, we have used a monoclonal antibody to the NGF receptor, 192 IgG, to immunocytochemically visualize and compare rat basal forebrain neurons responsive to NGF in aged (30 months) and young adult (10 months) rats. In a subpopulation of aged rats, NGF receptor-immunoreactive cells in the basal forebrain appear vacoulated and shrunken, and the neuropil staining is markedly reduced. While no substantial decline in cell density is apparent in Nissl-stained sections, the number of NGF receptor-positive cell profiles within the vertical limb of diagonal band nuclei is reduced by an average of 32% in aged rats. Marked reduction in the expression of NGF receptors in aged rats may signify loss of capacity of the basal forebrain neurons to bind and transport NGF from their terminals in the hippocampus and cortex, subsequent decrease in NGF delivered to the cell bodies, and eventual cellular dysfunction and death of neurons in aging.     

Developmental change in the nerve growth factor action from induction of choline acetyltransferase to promotion of cell survival in cultured basal forebrain cholinergic neurons from postnatal rats

Nerve growth factor (NGF), a well-characterized target-derived growth factor, has been postulated to promote neuronal differentiation and survival of the basal forebrain cholinergic neurons. In the present paper, we demonstrate that a developmental change in NGF action occurs in postnatal rat basal forebrain cholinergic neurons in culture. Firstly, NGF acts as maturation factor by increasing choline acetyltransferase (ChAT) activity and acts later as a survival factor. In dissociated cell cultures of septal neurons from early postnatal (P1-4) rats, ChAT activities were increased by the addition of NGF. That is, ChAT activities in P1 septal cells cultured for 7 days was increased 4-fold in the presence of NGF at a concentration of 100 ng/ml. However, the number of the acetylcholinesterase (AChE)-positive neurons was not significantly different between these groups. In contrast, septal neurons from P8 to P14 rats showed different responses to NGF. Although the P14 septal neurons in culture for 7 days without NGF lost about half of the ChAT activity during a 7-day cultivation, cells cultured with NGF retained the activity at the initial level. The number of AChE-positive neurons counted in cultures with NGF was much greater than the number without NGF. These results suggest that, during the early postnatal days, the action of NGF on the septal cholinergic neurons in culture changes from induction of ChAT activity to the promotion of cholinergic neuronal cell survival. During this developmental period in vivo, septal neurons are terminating their projections to the hippocampal formation. Similar NGF-regulated changes in cholinergic neurons were observed in cultured postnatal neurons from vertical limb of diagonal band. An analogy has been pointed out between the neuronal death of the basal forebrain cholinergic neurons and a similar neuronal death in senile dementia, especially Alzheimer's type. The work reported here might present a possibility that NGF could play a role in preventing the loss of the basal forebrain cholinergic neurons in this disease.     

Altered NGF protein levels in different brain areas after immunolesion

Nerve growth factor (NGF) provides critical trophic support to the cholinergic basal forebrain neurons that express high levels of the low-affinity NGF receptor (p75^NGFR) in the adult rat brain. Intraventricular injection of 192 IgG-saporin, made by coupling the monoclonal antibody to p75^NGFR 192 IgG to the cytotoxin saporin, selectively destroys the p75^NGFR-bearing neurons in the basal forebrain and was used here to examine the effects of selective cholinergic lesions on brain NGF protein levels. We showed that 192 IgG-saporin produced significant long-lasting elevation of NGF protein levels in the hippocampus, cortex, and olfactory bulb, with profound reductions of ChAT activities representing complete cholinergic deafferentations of these areas. NGF level was maintained in the basal forebrain, even though there was almost complete loss of p75^NGFR-immunoreactive cells and significant decrease of ChAT activity. In addition, a mild glial response was observed in the basal forebrain, and most of the activated astroglia expressed NGF-like immunoreactivity there. The increases in NGF protein levels in the target areas of the basal forebrain were most likely due to loss of cholinergic basal forebrain neurons and retrograde transport of NGF from these areas. Glial-derived NGF is partially responsible for the maintained level of NGF in the basal forebrain after the loss of cholinergic neurons. The accumulation of NGF protein in the target areas may have some effects on synaptic rearrangement in denervated tissues. © 1996 Wiley-Liss, Inc.     

Loss of NGF receptor immunoreactivity in basal forebrain neurons of aged rats: correlation with spatial memory impairment

Nerve growth factor (NGF) has recently been implicated as a trophic agent in the survival and maintenance of basal forebrain cholinergic neurons. To test the hypothesis that NGF may play a role in the age-related decline of cerebral cholinergic function and loss of cognitive ability, we investigated the possible correlation between the loss of basal forebrain neurons that stain for NGF receptor, and impairment of spatial reference memory performance in aged rats. Our results suggest that NGF receptor-positive basal forebrain neurons undergo marked cell atrophy and loss of neuropil staining in aged rats exhibiting impaired spatial learning and memory performance. Conversely, numerous, densely immunoreactive perikarya and a profuse neuritic plexus within the basal forebrain nuclei was consistently observed in behaviorally intact rats. Overall, the mean number of NGF receptor-positive basal forebrain neurons both in the nucleus of the diagonal band and nucleus basalis correlated with retention of the spatial task (r = 0.84 and r = 0.67, respectively; P less than 0.01). Our results support the view that progressive failure of retrograde trophic support due to the age-related loss of NGF receptors may promote degenerative changes in basal forebrain cholinergic neurons, and contribute to deterioration of cognitive ability in senescence.     

The cholinergic system, nerve growth factor and the cytoskeleton

Cholinergic neurons of the basal forebrain provide the major cholinergic innervation to the cortex and hippocampus, and play a key role in memory and attentional processes. Dysfunction of basal forebrain cholinergic neurons (BFCN) is a cardinal feature of Alzheimer's disease (AD) and correlates with cognitive decline. Survival of BFCN neurons depends upon binding of nerve growth factor (NGF), which is synthesized and secreted by cells in the cortex and hippocampus, with high-affinity (TrkA) and low-affinity (p75^NTR) neurotrophin receptors produced within BFCN neurons. NGF released from target cells activates TrkA on axon terminals and triggers activation of PI3K/Akt, MEK/ERK, and PLCγ (phospholipase C) signaling pathways. The signal then travels retrogradely along axon to cell body to promote neuronal survival. However, the nature of the retrograde signal remains mysterious. p75^NTR receptors could mediate a fundamentally different signaling pathway leading to apoptic cell death. Dysfunction of NGF and its receptors has been suggested to underlie the selective degeneration of the BFCN in end stage Alzheimer disease. In this regard, NGF, the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of AD. This review focuses on NGF-cholinergic dependency, NGF/receptor binding, signal transduction, retrograde transport, regulation of specific cellular endpoints, and the potential involvement of cytoskeleton dysfunction in defected NGF signaling.     

Decreased level of nerve growth factor (NGF) and its messenger RNA in the aged rat brain

Trophic factors such as nerve growth factor (NGF) are thought to support survival, differentiation and maintenance of neurons. Recent results indicate that NGF produced in cortical and hippocampal areas is required for the function of cholinergic neurons in the basal forebrain. With the use of enzyme immunoassay and RNA blot hybridization we studied the NGF protein and NGF mRNA, respectively, in regions of the brain innervated by basal forebrain cholinergic neurons in adult and aged rats. Levels of NGF protein were decreased by 40% in hippocampus of aged (28 months) Fischer 344 rats compared with adults (6 months), whereas no alterations were observed in cerebral cortex. Moreover, a reduction by 50% in the NGF mRNA was found in samples of the aged forebrain (cerebral cortex, hippocampus, basal forebrain and hypothalamus) compared to the adult. NGF deficiencies may thus account for the loss of cholinergic neurons in the basal forebrain generally found to accompany normal aging and resulting in altered cognitive functions.     

Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections

Several findings obtained in recent years suggest that NGF, aside from its well-established function as a neurotrophic factor for peripheral sympathetic and sensory neurons, also has trophic influence on the cholinergic neurons of the basal forebrain. The present study assessed whether NGF was able to affect survival of central cholinergic neurons after axonal transections in adult rats. The septo-hippocampal pathway was transected unilaterally by cutting the fimbria, and animals were implanted with a cannula through which NGF or control solutions were injected intraventricularly over 4 weeks. The lesions reduced the number of large cell bodies, as visualized by Nissl staining in the medial septal nucleus and in the vertical limb of the diagonal band of Broca. Furthermore, in the same nuclei, they reduced the number of cell bodies positively stained for AChE after pretreatment with diisopropylfluorophosphate (a method known to result in reliable identification of cholinergic neurons in the septal area). On lesioned sides, the number of cholinergic cells in medial septal nucleus and the vertical limb of the diagonal band was reduced by 50 +/- 4%, as compared to the number on contralateral sides. On lesioned sides of animals chronically treated with NGF, the number of AChE-positive cells in these areas was reduced only by 12 +/- 6%, as compared to control levels. These findings suggest that fimbrial transections resulted in retrograde degeneration of cholinergic septo-hippocampal neurons and that NGF treatment strongly attenuated this lesion-induced degeneration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease

Nerve growth factor (NGF) is important for regulation, differentiation, and survival of peripheral and central nervous system neurons, including basal forebrain cholinergic neurons (BFCN) which degenerate in Alzheimer's disease (AD). Mature NGF protein is processed from a larger precursor, proNGF. We demonstrate that proNGF is the predominant form of NGF in mouse, rat, and human brain tissue, whereas little or no mature NGF is detected. Previous reports showed NGF protein, measured by ELISA, is increased in AD BFCN target regions such as hippocampus and cortex. Using Western blotting, we demonstrate a twofold increase in proNGF in AD parietal cortex compared to controls, indicating that it is this precursor form, proNGF, that accumulates in AD. This increase may reflect either a role for biologically active proNGF or posttranslational disturbances in NGF biosynthesis that decrease the processing of proNGF to mature NGF in AD.     

Nerve growth factor enhances neurite arborization of adult sensory neurons; a study in single-cell culture

Nerve growth factor (NGF) is a well-established trophic factor of sympathetic and sensory neurons during development. NGF is, however, little known to be required for the maintenance or regulation of differentiated phenotypes of matured peripheral neurons. Since trophic factors, including NGF, are currently known to be secreted by non-neuronal cells, like Schwann cells and fibroblasts, a highly pure-neuron culture is required to assess the direct action of trophic factors on neurons. We have developed a single-neuron culture from neonatal and adult rat dorsal root ganglia in serum-free conditions, and estimated the primary effect of NGF on the morphological geometry of sensory neurons. We found that NGF promoted the neurite length of neonatal sensory neurons, rather than promoting arborization (branching of neurites), while in adult matured neurons NGF significantly enhanced neurite arborizations, rather than the maximal neurite extension, distance from the cell soma to the maximum margin of the territory of neurite extension. Total neurite length, the summed length of all neurites per neuron was significantly increased by NGF in both neonatal and adult neurons. NGF also increased the size of neuronal soma independent of neuronal maturation. Neonatal sensory neurons tended to die in 1 week despite the presence of NGF. In contrast, some adult sensory neurons were alive for more than 2 weeks in the absence of NGF. These results indicate that NGF more than simply accelerates a pre-existing developmental program in the matured stage, and that the promotion of neurite arborization by NGF in adult sensory neurons suggests that NGF may have some role in peripheral nerve regeneration via promotion of axonal sprouting.     

Basal forebrain magnocellular neurons stain for nerve growth factor receptor: correlation with cholinergic cell bodies and effects of axotomy

Recent evidence has demonstrated the presence of nerve growth factor (NGF) in areas of the central nervous system characterized by cholinergic innervation. We report that a unique population of rat basal forebrain magnocellular neurons that project to the cortex and hippocampus are immunoreactive to a monoclonal antibody to the NGF receptor. Removal of target contact results in a time-dependent loss or shrinkage of cells in the basal forebrain that stain for NGF receptor and acetylcholinesterase, suggesting that under normal conditions, basal forebrain cholinergic neurons utilize NGF for trophic support.