Basal forebrain neurons modulate the synthesis and expression of neuropeptides in the rat suprachiasmatic nucleus

We tested the hypothesis that efferents from the nucleus basalis magnocellularis (NBM) play a direct role in the regulation of neuropeptide synthesis and expression by neurons of the rat suprachiasmatic nucleus (SCN). Adult male rats in which the NBM was destroyed with quinolinic acid, either unilaterally or bilaterally, were compared with rats injected with physiological saline and with control rats. The estimators used to assess the effects of cholinergic deafferentation on the neuroanatomy and neurochemistry of the SCN were the total number of SCN neurons, the total number and somatic size of SCN neurons producing vasopressin (VP) and vasoactive intestinal polypeptide (VIP), and the respective mRNA levels. Bilateral destruction of the NBM did not produce cell death in the SCN, but caused a marked reduction in the number and somatic size of SCN neurons expressing VP and VIP, and in the mRNA levels of these peptides. The decrease in the number of VP- and VIP-producing neurons provoked by unilateral lesions was less striking than that resulting from bilateral lesions. It was, however, statistically significant in the ipsilateral hemisphere, but not in the contralateral hemisphere. The results show that the reduction of cholinergic inputs to the SCN impairs the synthesis, and thereby decreases the expression of neuropeptides by SCN neurons, and that the extent of the decline correlates with the amount of cholinergic afferents destroyed. This supports the notion that acetylcholine plays an important, and direct role in the regulation of the metabolic activity of SCN neurons.     

Nerve growth factor restores mRNA levels and the expression of neuropeptides in the suprachiasmatic nucleus of rats submitted to chronic ethanol treatment and withdrawal

Chronic ethanol treatment and withdrawal from alcohol decrease the synthesis and expression of neuropeptides in the hypothalamic suprachiasmatic nucleus. Given the existing evidence that neurotrophins modulate the synthesis and expression of neurotransmitters/neuromodulators in the mature brain, we have hypothesized that such alterations might result from the reduced biological activity or brain content of neurotrophic factors. To test this possibility, nerve growth factor (NGF) was delivered intraventricularly, over a 4-week period, to rats submitted to ethanol treatment for 6 months and to withdrawn rats. Vasopressin (AVP) and vasoactive intestinal polypeptide (VIP), and the respective mRNAs were detected by immunocytochemistry and in situ hybridization histochemistry, and their levels estimated using stereological methods and densitometry. In ethanol-treated and withdrawn rats, NGF produced increases in the number of AVP- and VIP-immunostained neurons to values identical to those of controls. Corresponding variations were detected in AVP and VIP mRNA levels, which indicates that NGF restored the expression of AVP and VIP by enhancing neuropeptide synthesis. These findings show that NGF can correct the changes induced by chronic ethanol treatment and withdrawal in the gene expression and protein content of the neuropeptides synthesized by suprachiasmatic neurons. They also reveal that NGF plays an important role in the maintenance of the neurochemical phenotype of the suprachiasmatic nucleus in the adult rat. Because suprachiasmatic neurons do not express trkA, NGF might have exerted its effects either through direct signalling of suprachiasmatic neurons via p75^NTR activation or, indirectly, by enhancing the activity of the cholinergic and/or glutamatergic afferents to the suprachiasmatic nucleus, or both.     

Vasoactive intestinal polypeptide neuron changes in the senile rat suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is thought to be the main neuronal oscillator underlying circadian rhythmicity of different biological phenomena such as sleep-wakefulness and body temperature. Although numerous studies in old rats showed that circadian organization is clearly disturbed in senescence, no decrease in total SCN cell number has been observed. However, in an earlier study we found a significant decrease of approximately 30% in the number of immunocytochemically-stained vasopressin (VP) neurons in the SCN of the old rat. The aim of the present study was to examine whether another group of SCN neurons, i.e., the vasoactive intestinal polypeptide (VIP) cells, shows age-related changes parallel with disturbances found in sleep/wake parameters. Immunocytochemical staining with antiVIP followed by morphometric analysis revealed a 36% decrease in the number of immunoreactive VIP neurons in the SCN of old rats as compared to young ones. The average size of the remaining VIP cells increased in aged rats. The rapid-eye-movement (REM)-sleep time was negatively correlated with the immunoreactive VIP cell number in the old animals. VP and VIP alterations in the SCN may constitute an anatomical substrate for the circadian disturbances observed in senescence.     

Lesions of the nucleus basalis magnocellularis in the rat: morphological, biochemical and behavioral reparative effect of nerve growth factor and ganglioside GM1

Three- and fifteen-month old rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM) were used. In 3-month old rats, 4 days after the lesion a 34 and 33% decrease in high affinity choline uptake (HACU) rate was found in the ipsilateral frontal and parietal cortices, respectively. Twenty-one days later the lesioned rats showed a loss in the NBM choline acetyltransferase (ChAT)-positive cells, a marked decrease in ipsilateral cortical ChAT activity and an impairment of the acquisition of a passive avoidance conditioned response. If the lesioned rats received nerve growth factor (NGF) (10 micrograms i.c.v.) twice a week or daily administration of ganglioside GM1 (GM1) (30 mg/kg i.p.), beginning immediately after surgery, the decreases in the HACU rate and ChAT activity were significantly smaller and the behavioral performance was normal. A potentiation by GM1 of NGF effects on the cholinergic neurons of the NBM occurred since no differences were detected between sham-operated rats and rats trated with NGF plus either the active (30 mg/kg) or inactive (10 mg/kg) dose of GM1. The loss in the number of NBM ChAT-positive neurons was reduced by GM1 or prevented by NGF administrations, indicating that the two drugs prevent the cholinergic deficit by protecting the cholinergic neurons of the NBM from ibotenic acid neurotoxicity. GM1 had no effect on ChAT activity decrease and behavioral impairment in 15-month old rats. The latter finding indicates an age-related loss of the ability of GM1 to enhance neurotrophic activity in the NBM.     

Neonatal exposure to monosodium glutamate induces morphological alterations in suprachiasmatic nucleus of adult rat

Neonatal exposure to monosodium glutamate (MSG) induces circadian disorders in several physiological and behavioural processes regulated by the suprachiasmatic nucleus (SCN). The objective of this study was to evaluate the effects of neonatal exposure to MSG on locomotor activity, and on morphology, cellular density and expression of proteins, as evaluated by optical density (OD), of vasopressin (VP)‐, vasoactive intestinal polypeptide (VIP)‐ and glial fibrillary acidic protein (GFAP)‐immunoreactive cells in the SCN. Male Wistar rats were used: the MSG group was subcutaneously treated from 3 to 10 days of age with 3.5 mg/g/day. Locomotor activity was evaluated at 90 days of age using ‘open‐field’ test, and the brains were processed for immunohistochemical studies. MSG exposure induced a significant decrease in locomotor activity. VP‐ and VIP‐immunoreactive neuronal densities showed a significant decrease, while the somatic OD showed an increase. Major axes and somatic area were significantly increased in VIP neurons. The cellular and optical densities of GFAP‐immunoreactive sections of SCN were significantly increased. These results demonstrated that newborn exposure to MSG induced morphological alterations in SCN cells, an alteration that could be the basis for behavioural disorders observed in the animals.     

Non-noxious skin stimulation activates the nucleus basalis of Meynert and promotes NGF secretion in the parietal cortex via nicotinic ACh receptors

The effects of non-noxious skin stimulation on nerve growth factor (NGF) secretion in the parietal cortex were examined in anesthetized rats. Innocuous skin stimulation was delivered to the left hindlimb with a soft-hair brush. Extracellular NGF in the right parietal cortex was collected by microdialysis methods using a protein-permeable probe and was measured using an enzyme-linked immune-sorbent assay. Brushing produced a significant increase in extracellular NGF levels. This NGF response was not observed in rats pretreated with a nicotinic ACh receptor (nAChR) antagonist mecamylamine. We further examined whether brushing could activate the basal forebrain nucleus (nucleus basalis of Meynert, NBM), which is the main source of cholinergic fibers in the cerebral cortex, by means of functional MRI. The blood oxygen level-dependent signal in the right NBM was significantly higher during brushing compared to baseline. The results suggest that non-noxious skin stimulation activates NBM and promotes NGF secretion in the parietal cortex via nAChRs.     

Nerve growth factor prevents cell death and induces hypertrophy of basal forebrain cholinergic neurons in rats withdrawn from prolonged ethanol intake

We have previously reported that the hippocampal cholinergic fiber network is severely damaged in animals withdrawn from ethanol, and that a remarkable recovery in fiber density occurs following hippocampal grafting, a finding that we suggested to be underpinned by the graft production of neurotrophic factors, which are known to be decreased after ethanol exposure. It is widely accepted that nerve growth factor (NGF) signals the neurons of the brain cholinergic system, including those of the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) nuclei, from which the septohippocampal projection arises. Because neurons in these nuclei are vulnerable to ethanol consumption and withdrawal we thought of interest to investigate, in withdrawn rats previously submitted to a prolonged period of ethanol intake, the effects of intraventricular delivery of NGF upon the MS/VDB cholinergic neurons. Stereological methods were applied to estimate neuron numbers and neuronal volumes in choline acetyltransferase (ChAT)-immunostained and Nissl-stained material. We have found that in ethanol-fed rats there was a significant reduction in the total number of Nissl-stained and cholinergic neurons in the MS/VDB, and that the suppression of ethanol intake further decreased neuron numbers. In addition, the somatic size of ChAT-IR neurons was reduced by ethanol intake, and withdrawal further aggravated neuronal atrophy. NGF treatment prevented the withdrawal-associated loss, and induced hypertrophy, of cholinergic neurons.These findings show that exogenous NGF protects the phenotype and prevents the withdrawal-induced degeneration of cholinergic neurons in the MS/VDB. These effects might be due to the trophic action of NGF upon the basal forebrain cholinergic neurons, including the hippocampal fiber network that conveys this neurotrophin retrogradely to the MS/VDB, and/or upon their targets, that is, the hippocampal formation neurons.     

Cell-type specific distribution of chloride transporters in the rat suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is a circadian oscillator and biological clock. Cell-to-cell communication is important for synchronization among SCN neuronal oscillators and the great majority of SCN neurons use GABA as a neurotransmitter, the principal inhibitory neurotransmitter in the adult CNS. Acting via the ionotropic GABA_A receptor, a chloride ion channel, GABA typically evokes inhibitory responses in neurons via Cl⁻ influx. Within the SCN GABA evokes both inhibitory and excitatory responses although the mechanism underlying GABA-evoked excitation in the SCN is unknown. GABA-evoked depolarization in immature neurons in several regions of the brain is a function of intracellular chloride concentration, regulated largely by the cation-chloride cotransporters NKCC1 (sodium/potassium/chloride cotransporter for chloride entry) and KCC1-4 (potassium/chloride cotransporters for chloride egress). It is well established that changes in the expression of the cation-chloride cotransporters through development determines the polarity of the response to GABA. To understand the mechanisms underlying GABA-evoked excitation in the SCN, we examined the SCN expression of cation-chloride cotransporters. Previously we reported that the K⁺/Cl⁻ cotransporter KCC2, a neuron-specific chloride extruder conferring GABA's more typical inhibitory effects, is expressed exclusively in vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP) neurons in the SCN. Here we report that the K⁺/Cl⁻ cotransporter isoforms KCC4 and KCC3 are expressed solely in vasopressin (VP) neurons in the rat SCN whereas KCC1 is expressed in VIP neurons, similar to KCC2. NKCC1 is expressed in VIP, GRP and VP neurons in the SCN as is WNK3, a chloride-sensitive neuron-specific with no serine–threonine kinase which modulates intracellular chloride concentration via opposing actions on NKCC and KCC cotransporters. The heterogeneous distribution of cation-chloride cotransporters in the SCN suggests that Cl⁻ levels are differentially regulated within VIP/GRP and VP neurons. We suggest that GABA's excitatory action is more likely to be evoked in VP neurons that express KCC4.     

Exogenous nerve growth factor stimulates choline acetyltransferase activity in aging Fischer 344 male rats

The effect of age and exogenous nerve growth factor (NGF) infusion on choline acetyltransferase (ChAT) specific activity is examined in microdissections of cerebral and hippocampal cortices, and the cholinergic nuclei of the medial septum and diagonal band of Broca (MS/DB), the nucleus basalis magnocellularis (NBM), and striatum of Fischer 344 male rats. Significant, 20% losses in ChAT activity are found in the MS/DB and striatum of 24-month-old rats (n = 21) compared to 4-month-old animals, but there is no apparent loss of enzyme activity in the NBM. Loss of ChAT activity in the MS/DB is only observed in animals older than 19 months of age, while a striatal deficit is found in animals older than 7 months. Treatment for 2 weeks with NGF at 1.2 micrograms/day results in significant 70% increases of ChAT activity in the MS/DB and striatum of 24-month-old rats compared to untreated and vehicle-treated 4-month-old rats, but does not stimulate activity in the NBM. Sensitivity of ChAT activity in the MS/DB and striatum to exogenous NGF increases with age. These experiments indicate that in the MS/DB, NBM, and striatum of Fischer 344 male rat there is an age-associated, differential regulation of ChAT enzyme activity and sensitivity to exogenous NGF.     

树、大鼠、豚鼠视交叉上核加压素免疫阳性神经元分布的差异性比较

目的 :观察加压素免疫阳性 (VP IR)神经元在树下丘脑视交叉上核中的分布并与其在大鼠豚鼠视交叉上核中的分布进行比较 ,探讨VP IR神经元分布的种属差异性。方法 :树、大鼠、豚鼠内固定后恒冷箱冰冻连续切片 ,免疫组织化学PAP法染色。结果 :三种动物的视交叉上核形状不同 ,VP IR神经元在三种动物视交叉上核中的分布位置、数量和密度不同 ,此外 ,在豚鼠两侧视交叉上核间以及第三脑室底部与视交叉正中背侧之间 ,还观察到一些散在分布的VP IR神经元 ,而树和大鼠相应区域却未见有VP IR神经元分布。结论 :VP IR神经元在视交叉上核中的分布有较大的种属差异性     

Lesion of the nucleus basalis magnocellularis does not affect cerebral cortical blood flow in rats.

The effects of a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM) on blood flow of the cerebral cortex and striatum were studied at 2, 4, 8 and 16 weeks after the lesion in conscious rats. In the cerebral cortex, no side-to-side difference in blood flow was observed, though cholinergic enzyme activity was markedly reduced on the side of the lesion. The results suggest that NBM lesion produces disturbance of cholinergic neurons in the cerebral cortex without significant alteration of blood flow.     

Immunohistochemical evidence for the presence of neuropeptides in the hypothalamic suprachiasmatic nucleus of ground squirrels

The cytoarchitecture and immunocytochemical distribution of neuropeptides (corticotropin-releasing factor, CRF; neuropeptide Y, NPY; oxytocin, OXY; vasopressin, VP; and vasoactive intestinal polypeptide, VIP) were studied in the hypothalamic suprachiasmatic nuclei (SCN) in male and female ground squirrels of two species (Spermophilus tridecemlineatus and S. richardsonii). Immunoreactive (IR) perikarya were found in sections incubated with VP or VIP antisera. VP-IR cell bodies were seen in the dorsal and medial parts of the nucleus in colchicine-treated animals. IR fibers were distributed throughout the SCN. In the ventral part of the nucleus, VIP-IR cells were seen in untreated animals and were more pronounced in colchicine-treated animals. VIP-IR fibers and terminals form a dense plexus throughout the nucleus. Furthermore, NPY-IR terminals and fibers with multiple varicosities, but no IR perikarya, were present in the suprachiasmatic nuclei. Within the borders of the SCN, no cell bodies or fibers were stained with CRF or OXY antisera in any animal.     

Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats

Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals.     

Light stimulation of the hypothalamic neuroendocrine system.

This paper demonstrates that, in the mediation of light, the suprachiasmatic nucleus (SCN) functionally associates with the anterior periventricular and parvocellular paraventricular neuron systems in rats. Intact rats (group 1) and rats undergoing a hemicomplete cutting of the SCN (group 2) were housed in a dark room (2-3 weeks) and killed after an exposure to light for 10, 30 or 60 min. Other intact animals (group 3) kept in a dark room (2 weeks) were exposed to light for 10 min, then stored 60 min in the dark room, and killed in darkness. The SCN, anterior periventricular nucleus, and parvocellular paraventricular nucleus were examined immunohistochemically using antisera for vasoactive intestinal polypeptide (VIP), arginine vasopressin, somatostatin, rat corticotropin releasing factor (rCRF), and c-fos protein. In comparison with animals kept in darkness, animals exposed for 10 and 30 min to light indicated a remarkable reduction of VIP immunoreactivity in the SCN and some increase of CRF immunoreactivity in the parvocellular paraventricular nucleus. The diminution of VIP immunoreactivity did not occur in the isolated SCN of group 2 animals. In group 3, a 10 min-light exposure induced a remarkable enhancement of nuclear c-fos immunoreactivity in neurons in the ventrolateral region of the SCN, in the anterior periventricular nucleus, and in the parvocellular paraventricular nucleus, most strongly in the SCN. Double immunolabeling methods have shown that VIP, somatostatin, and CRF neurons in the respective nuclei were c-fos positive.     

Amelioration of cholinergic neurons dysfunction in aged rats depends on the continuous supply of NGF

The present study was designed to examine whether NGF-induced improvement in morphology of senile basal forebrain cholinergic neurons persist after discontinuation of NGF treatment. Trophic effect of continuous intraventricular infusion of NGF was tested in the 4- and 28 months old male Wistar rats immediately after cessation of NGF and 3 or 6 weeks after termination of treatment. Immunohistochemical procedure for ChAT, TrkA, and p75(NTR) receptor has been applied to identify cholinergic cells in the basal forebrain structures. Using the quantitative image analyzer, morphometric and densitometric parameters of cholinergic cells were measured. In untreated 28-month-old rats a reduction in the number, size and intensity of staining of cholinergic neurons was observed in all basal forebrain structures. NGF significantly improved morphological parameters of ChAT- and TrkA-positive cells in aged rats. In 28-month-old rats tested within 3 and 6 weeks after discontinuation of infusion a renewed progressive deterioration of cholinergic phenotype of basal forebrain neurons was observed when compared with the NGF-treated immediately tested group. The parallel staining for p75(NTR) revealed normal morphology of the basal forebrain neurons, despite of the age of rats or the NGF treatment. Analysis of Nissl stained sections also showed that 28-month-old rats did not display significant losses of neurons in the basal forebrain when compared with the young animals. These findings demonstrate that senile impairment of cholinergic neurons is induced by a loss of cholinergic phenotype rather than an acute degeneration of cell bodies. NGF may be beneficial in enhancing cholinergic neurochemical parameters, but the protective effects seem to be dependent on the continuous supply of NGF.     

Effect of nucleus basalis magnocellularis cholinergic lesions on fear-like and anxiety-like behavior

Previous research has suggested that cholinergic neurons in the nucleus basalis magnocellularis and substantia innominata (NBM/SI) may be important in mediating aversive states. The authors investigated the effect of NBM/SI cholinergic lesions, induced with 192 IgG saporin, on behavioral measures of aversive states in rats. Behavior in the elevated plus maze and behavioral suppression induced by 2 fear-conditioned stimuli, a tone and a light, were evaluated. Lesions had no effect on any measures in the elevated plus maze but attenuated operant suppression induced by the light and attenuated freezing induced by the tone, though this last effect was not statistically significant. The results of the study suggest that NBM/SI cholinergic neurons may be important in mediating selective aspects of aversive states.     

Age-dependent cerebral metabolic effects of unilateral nucleus basalis magnocellularis ablation in rats

To investigate the age-dependent functional importance of cholinergic neocortical inputs, and to explore whether cortical cholinergic denervation in aged animals might better model the cerebral metabolic changes of Alzheimer's disease, the effects of unilateral ablation of the nucleus basalis magnocellularis (NBM) on cerebral glucose metabolism were studied in young and aged rats. Regional cerebral metabolic rates for glucose (rCMRglc) were determined, using the [14C]deoxyglucose method, in 48 brain regions of 3- and 24-month old Fischer-344 rats at 3, 7, 14 and 28 days after stereotaxic injection of ibotenate into the right NBM, and in sham-operated animals at 3 and 14 days later. For both ages the peak effect of unilateral NBM ablation occurred 3 days later: in young rats, rCMRglc was significantly reduced (compared to the contralateral side) in all 24 anterior cortical areas examined (mean decline 20%), whereas in aged animals, only 9 of 24 areas showed a significant decline in glucose utilization, and the magnitude of rCMRglc reduction (9%) was smaller. Near complete recovery of rCMRglc occurred by 7 days in young and old rats. We conclude that the basalocortical cholinergic projection plays a smaller role in neocortical function of aged rats, possibly because its tonic activity is reduced. Both young and aged rats undergo cortical metabolic normalization after unilateral NBM ablation; hence the NBM-lesioned aged rat is not a better model of the progressive decline in rCMRglc that occurs in Alzheimer's disease.     

Effects of nerve growth factor and GM1 ganglioside on the number and size of cholinergic neurons in rats with unilateral lesion of the nucleus basalis

Four groups of rats with a unilateral ibotenic acid lesion of the nucleus basalis were treated with saline, nerve growth factor (NGF) 10 micrograms administered intracerebroventricularly twice per week, sialoganglioside GM1 30 m/kg daily i.p. and NGF twice per week plus GM1 10 mg/kg i.p. daily, respectively, beginning immediately after lesioning. Twenty-one days later the rats treated with saline showed a marked impairment in negotiating a 'step through' passive avoidance conditioned response, a 32% decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the lesioned nucleus basalis and a 12% decrease in their areas. The rats treated with NGF and NGF plus GM1 showed no difference from sham-operated rats. In the GM1-treated rats a 12% decrease only in the number of ChAT-positive neurons was detected while performance and neuronal areas were normal. These findings indicate that NGF and GM1 prevent the cholinergic deficit by protecting the cholinergic neurons of the nucleus basalis from ibotenic acid neurotoxicity.     

Microanatomical and electrophysiological changes of the rat dentate gyrus caused by lesions of the nucleus basalis magnocellularis

The effect of unilateral or bilateral lesions of the nucleus basalis magnocellularis (NBM) on the dentate gyrus of the hippocampus were assessed using microanatomical and electrophysiological techniques. NBM is the main cholinergic basal forebrain nucleus that supplies the fronto-parietal cortex. Lesions were induced using the neurotoxin ibotenic acid or a radio-frequency system and did not affect glutamic acid decarboxylase activity both in the frontal cortex and in the hippocampus. At 4 weeks after lesioning, a loss of choline acetyltransferase (ChAT) activity and of ChAT-immunoreactive fibres was observed in the frontal cortex but not in the hippocampus and no changes in the density of granule neurons of the dentate gyrus or in the hippocampal long-term potentiation (LTP) were noticeable. At 8 weeks after lesioning the loss of both ChAT activity and of ChAT-immunoreactive fibres persisted in the frontal cortex of NBM-lesioned rats. Moreover, at this time a significant decrease in the density of granule neurons in the dentate gyrus accompanied by a reduced probability of dentate LTP induction were observed in both ibotenic acid- and radio-frequency-lesioned rats. These findings have shown that although NBM does not send direct cholinergic projections to the hippocampus, lesions of this cholinergic nucleus are accompanied by delayed neurodegenerative changes involving the dentate gyrus. This suggests the occurrence of indirect connections between NBM and the hippocampus, the functional relevance of which should be explored.     

NADPH-diaphorase histochemistry in the rat cerebral cortex and hippocampus: effect of electrolytic lesions of the nucleus basalis magnocellularis

Unilateral or bilateral electrolytic lesions of the nucleus basalis magnocellularis (NBM) increased NADPH-diaphorase in the fronto-parietal cortex and in the CA1-CA3 fields of the hippocampus. NBM is the cholinergic basal forebrain nucleus supplying the fronto-parietal cortex but not the hippocampus. This increase was more remarkable at 4 weeks than at 2 weeks after lesioning. Monolateral or bilateral lesioning of the NBM increased to a similar extent NADPH-diaphorase. The number of neurons expressing NADPH-diaphorase was not statistically different between sham-operated and NBM-lesioned rats. These results indicate that similarly as reported in experimental damage of several brain areas, lesions of the NBM induce NADPH-diaphorase. The induction of this marker for nitric oxide synthase occurs both in the target of projections arising from the NBM such as the frontal cortex and in an area not directly supplied by NBM such as the hippocampus. Lesion-induced NADPH-diaphorase increase may contribute to neurodegenerative changes caused by damage of the NBM area.