Effects of nerve growth factor on behavioral recovery following caudate nucleus lesions in rats

Rats with bilateral lesions of the caudate nucleus received intracaudate injections of either nerve growth factor protein (NGF) or inert buffer immediately following surgery. NGF-treated animals demonstrated a faster recovery of normal appetitive behavior and perseverated less than their buffer-treated counterparts on a spatial reversal task, but both groups were impaired relative to sham controls on acquisition of an active avoidance response. Glia to neuron ratios were significantly increased in both lesion groups when compared with sham controls. However, this increase was less in the NGF-treated animals than in the buffer-treated animals. NGF treatment had no effect on steady-state caudate dopamine levels, measured six months after surgery.     

Effects of brain-derived neurotrophic factor and nerve growth factor on remaining neurons in the lesioned nucleus basalis magnocellularis

Rats received a unilateral lesion of the nucleus basalis magnocellularis (NBM) by infusion of ibotenic acid. Starting 2 weeks after the lesion, the animals were treated with nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) by intraparenchymal infusion of 3 μg per day for 4 weeks. Lesioned control animals received a similar amount of cytochromec. The activity of cholone acethyltransferase (ChAT) in the frontal neocortex was signigicantly reduced by the lesion (−39%). However, the intraparenchymal treatment with NGF or BDNF did not affect cortical ChAT activity. The number of p75 NGF receptor-immunoreactive neurons in the NBM was significantly decreased (−49%) by the lesion and was not affected by NGF or BDNF. The size of the remaining neurons was significantly increased by NGF (+32%), but not by BDNF (+12%). Similarly, in situ hybridization showed enhanced expression of the p75 NGF receptor following treatment with NGF, but not with BDNF. These results suggest that although BDNF occurs in the target area of cholinergic NBM neurons, its effects on these neurons are less pronounced than those of NGF.     

Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis

Monosialoganglioside GM₁ and nerve growth factor (NGF) were administered alone or concomitantly to adult male rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM). High-affinity choline uptake (HACU) rate and choline acetyltransferase (ChAT) activity were measured, 4 and 21 days after surgery, respectively, in the frontal and parietal cortices of both hemispheres. A 33–34% decrease in HACU rate and a 43-39% decrease in ChAT activity was found in the ipsilateral cortices 4 and 21 days, respectively, after the lesion. If the lesioned rats received NGF (10 μg i.c.v.) twice a week or daily administrations of GM₁ (30 mg/kg, i.p.), beginning immediately after surgery the decrease in HACU rate and ChAT activity was smaller. If NGF and GM, were given concomitantly no decrease in HACU rate and ChAT activity was detected in the lesioned hemisphere and a slight increase occurred in the contralateral hemisphere. However, after the concurrent administration of NGF (10 μg i.c.v.) and the inactive dose of GM₁ 10 mg/kg i.p. no decrease in HACU and ChAT activity was also found in the lesioned rats. The latter finding indicates a potentiation by GM₁ of NGF effects on the cholinergic neurons of the IBM. The two drugs may either antagonize the neurotoxic effects of ibotenic acid or stimulate a compensatory activity in the remaining neurons.     

Immunoelectron microscopic evidence of nerve growth factor receptor metabolism and internalization in rat nucleus basalis neurons

Nerve growth factor receptor (NGFr) immunoreactive neurons of the adult rat nucleus basalis magnocellularis were examined by electron microscopy. Prominent NGFr immunoreactivity (IR) was consistently present along the perikaryal cell membrane and frequently in intracellular sites of protein synthesis and modification such as the rough endoplasmic reticulum and Golgi apparatus, respectively. Immunoperoxidase reaction product was also seen along the nuclear membrane. Membrane-bound aggregates of immunoreactive vesicles were scattered throughout the perikaryon, being more concentrated in the perinuclear region and in the proximal neurites. These may represent either aggregates of receptor-containing vesicles on their way to/from the cell membrane or secondary lysosomes where NGFr reaction product is degraded. Immunostained cytoplasmic vesicles which possessed an electron-dense coat and were adjacent to or contiguous with the plasmalemma probably represented internalized receptor. This ultrastructural study of the subcellular distribution of NGFr-IR in basal forebrain neurons therefore demonstrates sites of receptor metabolism and potential receptor-ligand interaction.     

Partial reversal of lesion-induced deficits in cortical cholinergic markers by nerve growth factor

Nerve growth factor (NGF) was injected into the lateral ventricle (5 μg on 4 occasions) of rats which had previously sustained ibotenic acid-induced lesions of the nucleus basalis of Meynert. Lesioned, but vehicle-injected and sham-lesioned and vehicle-injected rats were run as controls. Infusion of NGF led to a significant recovery of cortical choline acetyltransferase and acetylcholinesterase activity 6 weeks, but not two weeks after the lesion.     

Effects of chronic infusion of nerve growth factor (NGF) in rats with nucleus basalis magnocellularis lesion

We attempted to evaluate the effects of bilateral injection of ibotenic acid (IA) into the nucleus basalis magnocellularis (nbm) of rats as well as the potential recovery mediated by the infusion of nerve growth factor (NGF). The lesion caused an impairment of learning and memory processes. Also, a severe depletion of choline acetyl transferase activity was detected in cortical areas. After the NGF administration, a significant reversion of these functional changes was observed. Thus, IA-lesioned rats might serve as a model for the evaluation of neurotrophic factors actions on basal forebrain damaged neurons.     

Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis

Monosialoganglioside GM₁ and nerve growth factor (NGF) were administered alone or concomitantly to adult male rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM). High-affinity choline uptake (HACU) rate and choline acetyltransferase (ChAT) activity were measured, 4 and 21 days after surgery, respectively, in the frontal and parietal cortices of both hemispheres. A 33–34% decrease in HACU rate and a 43-39% decrease in ChAT activity was found in the ipsilateral cortices 4 and 21 days, respectively, after the lesion. If the lesioned rats received NGF (10 μg i.c.v.) twice a week or daily administrations of GM₁ (30 mg/kg, i.p.), beginning immediately after surgery the decrease in HACU rate and ChAT activity was smaller. If NGF and GM, were given concomitantly no decrease in HACU rate and ChAT activity was detected in the lesioned hemisphere and a slight increase occurred in the contralateral hemisphere. However, after the concurrent administration of NGF (10 μg i.c.v.) and the inactive dose of GM₁ 10 mg/kg i.p. no decrease in HACU and ChAT activity was also found in the lesioned rats. The latter finding indicates a potentiation by GM₁ of NGF effects on the cholinergic neurons of the IBM. The two drugs may either antagonize the neurotoxic effects of ibotenic acid or stimulate a compensatory activity in the remaining neurons.     

Lack of correlation between cortical levels of choline acetyltransferase and learning scores in rats with globus pallidus lesions

Previous work has shown that rats with lesions of the globus pallidus (GP) exhibit a generalized learning impairment. Data are presented suggesting that this impairment is not due to inadvertent damage to the nucleus basalis magnocellularis. Rats with GP lesions evidenced a significant visual discrimination learning loss and a significant reduction in cortical choline acetyltransferase (ChAT) activity. However, there was no significant correlation between the severity of the learning loss and the amount of reduction of cortical ChAT activity.     

Biphasic effects of ethanol on acetylcholine release in the rat prefrontal cortex

Low doses of ethanol (0.5 g/kg i.p.) increased, while higher doses (1 g/kg i.p.) reduced acetylcholine (ACh) release in the rat prefrontal cortex (PFC). Ethanol (50-300 mM) applied in the nucleus basalis through a second dialysis probe caused concentration-dependent biphasic changes in prefrontocortical ACh release. Ethanol apparently acts on cholinergic fibers to modulate ACh transmission in the PFC. These results could be of relevance for the bidirectional modulation of working memory by ethanol.     

Changes in cortical EEG and cholinergic function in response to NGF in rats with nucleus basalis lesions

We examined whether recovery of cholinergic function in response to nerve growth factor (NGF) results in restoration of electrocortical activity. Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with NGF or vehicle. Cortical electrical activity was assessed at postoperative days 4, 7, 14, and 21 from 8 epidural electrodes. On day 21, choline acetyl transferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in increases in slow-wave (δ) power and decreases in high-frequency (β₂) power in the lesioned, as well as the non-lesioned hemisphere. Changes correlated topographically and in magnitude with losses of ChAT activity and suggested that regional electrocortical function was affected by cholinergic activity originating in the ipsilateral, as well as the contralateral hemisphere. NGF attenuated changes in cholinergic and electrocortical function bilaterally, though in the lesioned hemisphere, function did not return to control levels. Likewise, intact animals receiving NGF showed increases in β₂-power, as well as modest increases in ChAT activity. Changes in brain electrical activity in response to NGF occurred within 4–7 days without significant changes during the 2 weeks thereafter. Our results suggest that outcomes of future animal and human trials using unilateral i.c.v. infusions of NGF need to consider the reciprocal influences of hemispheric cholinergic function, as well as possible effects of NGF on intact brain.     

Relationship between asymmetries in striatal dopamine release and the direction of amphetamine-induced rotation during. The first week following a unilateral 6-OHDA lesion of the substantia nigra

In animals with a large unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) system the traditional “rotational behavior model” states that amphetamine will induce circling behavior towards the denervated striatum (ipsiversive), that is, away from the side where there is greater amphetamine-stimulated DA release and greater DA receptor stimulation. It is puzzling, therefore, why amphetamine induces contraversive rotation in rats tested 4 days after a unilateral 6-OHDA lesion, despite a 90-95% loss of the dopaminergic input to the striatum by this time. Rats reverse their direction of amphetamine-induced rotation by 8 days post-lesion and turn in the ipsiversive direction thereafter. To try and resolve this paradox, bilateral striatal microdialysis was used to estimate the effects of amphetamine on DA neurotransmission on Day 4 and Day 8 following a large unilateral 6-OHDA lesion of the substantia nigra. On Day 4 post-lesion, amphetamine produced a moderate (around 50% of control) increase in the extracellular concentration of DA in the denervated striatum. This amphetamine-releasable pool of DA was exhausted by a single amphetamine challenge, because a second injection of amphetamine given 3 h after the first did not produce a comparable increase in DA. It is suggested that on Day 4 post-lesion the amount of DA released by amphetamine in the denervated striatum is sufficient to produce greater DA receptor stimulation on that side, because of DA receptor supersensitivity, and this leads to contraversive rotation. On Day 8 post-lesion, amphetamine induced DA release in the intact striatum but had no effect on extracellular DA in the denervated striatum (DA was nondetectable). On Day 8, therefore, DA receptor stimulation would be greatest in the intact striatum, leading to ipsiversive rotation. In conclusion, it is suggested that the seemingly paradoxical reversal in the direction of amphetamine-induced rotation that occurs over the first week following a unilateral 6-OHDA lesion is consistent with the traditional rotational model, and is due to time-dependent changes in the ability of amphetamine to release DA in the denervated striatum. © 1994 Wiley-Liss, Inc.     

Alterations in dendritic morphology of frontal cortical neurons after basal forebrain lesions in adult and aged rats

The nucleus basalis magnocellularis (NBM) is the major cholinergic projection to neocortex in the rat and plays a role in the modulation of cortical activity. Lesions of the NBM decrease thickness of lamina II–III of frontal cortex and decrease soma size of lamina II–III neurons. Additionally, aging produces changes in neuron size and numbers in the basal forebrain and frontal cortex of rats. We assessed dendritic changes in neurons from lamina II–III of frontal cortex in adult, middle-aged, and aged rats three months after unilateral lesions of the NBM. While lesions did not affect dendritic morphology in young adult rats, they decreased total dendritic length in middle-aged and aged rats, with dendritic alterations most pronounced in middle-aged rats. In middle-aged rats, lesion-induced changes in basilar arbor were apparently due to decreased dendritic branching: lesions markedly decreased the number of first-, second-, and third-order branches, but did not affect higher-order branching. In aged rats, lesions resulted in a small decrease in dendritic material proximal to the soma and a pronounced decrease in dendritic material distal to the soma, apparently due to a decrease in the length of terminal branches. These results suggest that the plasticity of neocortical neurons in the basalocortical system changes with age, and that early in aging this system may be particularly vulnerable to neural damage.     

Effects of local release of hepatocyte growth factor on peripheral nerve regeneration in acellular nerve grafts

Options for reconstructing peripheral nerve gaps after trauma are limited. The acellular nerve is a new kind of biomaterial used to reconstruct the peripheral nerve defect, but its use could be improved upon. We aimed to investigate the effect of adenoviral transfection with hepatocyte growth factor (HGF) on the functional recovery of transected sciatic nerves repaired by acellular nerve grafting. 30 Rats were divided into three groups (10/group) for autografting and acellular grafting, as well as acellular grafting with adenovirus transfection of HGF (1 × 10⁸ pfu) injected in muscles around the proximal and distal allograft coapation. Sciatic functional index (SFI) was evaluated every 4 weeks to week 16 by measuring rat footprints on walking-track testing. The three groups presented initial complete functional loss, followed by slow but steady recovery, with final similar SFIs. Weight of the gastrocnemius and soleus muscles, histologic and morphometric study and neovascularization in the nerve grafts were evaluated at week 16. Autografting gave the best functional recovery, but HGF-treated acellular grafting gave better recovery than acellular grafting alone. Neovascularization was greater with HGF-treated acellular grafting than with autografting and acellular grafting alone. Axonal regeneration distance of autografting on the 20th postoperative day was the longest in the three groups,while that of acellular grafting alone was the smallest. Acellular nerve grafting may be useful for functional peripheral nerve regeneration, and with human HGF gene transfection may improve on acellular grafting alone in functional recovery.     

Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats.

The effects of chronic intermittent administration (7 months) of two neuroleptics, haloperidol (HAL) and raclopride (RAC), were compared using several different measures. Both drugs were administered weekly by subcutaneous injection at 7.0 mg/kg. Both neuroleptics consistently produced catalepsy throughout the treatment period, although HAL was generally more cataleptogenic than RAC. Assessment of dopamine (DA) release in the caudate putamen (CPu), through the use of in vivo microdialysis, showed that chronic HAL or RAC administration caused a prolonged decrease of DA release in response to a low dose of the DA D2 agonist quinpirole (0.03 mg/kg, sc). Injection of the muscarinic agonist pilocarpine (1.0 mg/kg, IP) did not have any significant within-group effects, although both neuroleptic treatment groups showed decreased DA release when compared to controls. Ultrastructural analysis of the dorsolateral CPu showed that both HAL and RAC treatment resulted in a significant increase in the number of perforated synapses, which contain a discontinuous density along the postsynaptic membrane. These results demonstrate that two different DA D2 receptor antagonists produce a similar effect on DA function and ultrastructural changes within the CPu following chronic, intermittent treatment.     

Effects of nerve growth factor on TTX- and capsaicin-sensitivity in adult rat sensory neurons

We have investigated the effects of nerve growth factor (NGF, 2.5 ng/ml for 1–2 weeks) on enriched adult rat dorsal root ganglion (DRG) neurons maintained in cell culture in defined media. Whole-cell recordings in cells cultured in the absence and presence of NGF revealed no significant difference in resting membrane potential and input resistance. However, the threshold for spike generation was significantly lower in untreated cells than in treated cells; −25 ± 1.1mV vs−19 ± 2.2mV, respectively. The sensitivity of the Na⁺ spike to tetrodotoxin (TTX, 1 μM) was different in cells cultured in the absence or presence of NGF. For example, spikes were abolished by TTX in 100% of untreated cells, while in NGF-treated cells the spike was abolished in only 41% of the neurons. Chemosensitivity of DRG neurons was also different in the absence and presence of NGF. For example, the percent of neurons in which a current activated by 8-methyl-N-vanillyl-6-nonenamide (capsaicin, 500 nM) was detected, increased from 18% in untreated cells to 55% in NGF-treated cells. NGF did not influence the number of cells surviving. The results indicate that NGF can regulate TTX and capsaicin sensitivity in these adult rat sensory neurons. Our experimental protocol indicates that this effect is not mediated by a factor in the serum or released from non-neuronal cells.     

Effects of cocaethylene on dopamine and serotonin synthesis in Long–Evans and Sprague–Dawley brains

We examined the behavioral and neurochemical effects of cocaethylene treatment in Long–Evans (LE) and Sprague–Dawley (SD) rats. Cocaethylene-induced behaviors were significantly less in LE rats. Cocaethylene caused an inhibition of dopamine synthesis in the caudate nucleus and nucleus accumbens that was equivalent in both rat lines. Serotonin synthesis was also suppressed by cocaethylene treatment, however this phenomenon was less pronounced when compared with the effects on dopamine synthesis.     

NMDA and dopamine interactions in the nucleus accumbens modulate cortical acetylcholine release

The nucleus accumbens (NAC) plays a key role in directing appropriate motor output following the presentation of behaviorally relevant stimuli. As such, we postulate that accumbens efferents also participate in the modulation of neuronal circuits regulating attentional processes directed toward the identification and selection of these stimuli. In this study, N-methyl-d-aspartate (NMDA) and D1 ligands were perfused into the shell region of the NAC of awake rats. Cortical cholinergic transmission, a mediator of attentional processes, was measured via microdialysis probes inserted into the prefrontal cortex (PFC). NMDA perfusions (150 or 250 microm) into NAC resulted in significant increases in acetylcholine (ACh) efflux in PFC (150-200% above baseline levels). Co-administration of the D1 antagonist SCH-23390 (150 microm) markedly attenuated (by approx. 70%) ACh efflux following perfusions of 150 microm NMDA but not following 250 microm NMDA, suggesting that D1 receptor activity contributes to the ability of the lower but not the higher concentration of NMDA to increase cortical ACh release. Collectively, these data reveal a positive modulation of NMDA receptors by D1 receptors in NAC that is expressed trans-synaptically at the level of cortical transmission. This modulation may underlie the coordinated linking of attentional processes and motor output following exposure to salient and behaviorally relevant stimuli.     

神经生长因子对糖尿病神经病变大鼠神经肽和神经传导速度的影响

目的 探讨神经生长因子对糖尿病周围神经病变大鼠神经肽和神经传导速度的影响. 方法 雄性Wistar大鼠35只按随机数字表法分为健康对照组(n=10)、糖尿病模型组(n=13)和神经生长因子治疗组(n=12),后两组用链脲佐菌素制成糖尿病周围神经病变大鼠模型,并给予神经生长因子治疗组神经生长因子治疗(40μg/kg).显微镜下观察并计算背根神经节中P物质、降钙素基因相关肽(CGRP)免疫阳性细胞率,检测运动神经传导速度(MNCV)和感觉神经传导速度(SNCV). 结果 糖尿病模型组大鼠背根神经节中P物质、CGRP免疫阳性细胞率(27.710％±3.471％;36.360％±12.027％)以及神经生长因子治疗组治疗前MNCV [(35.80±6.19) m/s]、SNCV[(39.62±6.69) m/s]与健康对照组[P物质:44.225％±8.213％;CGRP:47.400％±13.723％;MNCV:(55.83±10.30) m/s; SNCV:(47.02±7.52) m/s]相比显著下降,差异有统计学意义(P＜0.05).经神经生长因子治疗后,P物质、CGRP免疫阳性细胞率(49.417％±6.753％;53.811％±7.125％)较糖尿病模型组显著增高,MNCV[(41.80±3.45) m/s]、SNCV[(42.92±6.69) m/s]均治疗前显著增高,差异有统计学意义(P＜0.05). 结论 糖尿病周围神经病变大鼠可出现神经传导速度下降和神经生长因子相关神经肽P物质、CGRP缺乏,而神经生长因子可促进神经肽的表达并提高神经传导速度.     

Transplantation of embryonic ventral forebrain grafts to the neocortex of rats with bilateral lesions of nucleus basalis magnocellularis ameliorates a lesion-induced deficit in spatial memory

Embryonic ventral forebrain grafts containing developing cholinergic cells were transplanted to the neocortex of rats with bilateral quisqualic acid lesions of the nucleus basalis magnocellularis. A lesion-induced deficit on performance of a spatial alternation test of memory was reduced by such transplants. When the same animals were treated with the acetylcholinesterase inhibitor physostigmine (0.05 mg/kg), however, performance on the behavioral task was not further promoted, and therefore, under these conditions, the cholinergic cortical transplants appear not to be subject to modulation by anticholinesterase drugs.