氧化应激在慢性缺血性脑白质损伤中的作用

目的 阐明氧化应激是否参与大鼠慢性脑缺血所致的脑白质损伤.方法 健康雄性Wistar大鼠按照完全随机数字表法分为假手术组,持久性双侧颈总动脉结扎3 d组、7 d组、3周组及6周组,每组6只.应用大鼠双侧颈总动脉结扎制备慢性脑缺血模型,检测大鼠脑白质内超氧化物歧化酶(SOD)活性、过氧化氢酶(CAT)活性、谷胱甘肽(GSH)含量以及脂质过氧化产物丙二醛(MDA)和4-羟基壬烯醛(4-HNE)加合物的变化.结果 与假手术组比较,慢性脑缺血大鼠脑白质内MDA含量在手术后3周明显增加,手术后6周进一步增高,差异有统计学意义(P<0.05).手术后3d至6周,慢性脑缺血大鼠脑白质内4-HNE蛋白加合物逐渐增高,与假手术组比较有差异有统计学意K(P<0.05).SOD活性在手术后3周和6周才明显降低,与假手术组比较差异有统计学意义(P<0.05).此外,慢性脑缺血大鼠脑白质内GSH含量在手术后7d即开始降低,而在手术后3周及6周则进一步下降,与假手术组比较差异有统计学意义(P<0.05).结论 慢性脑缺血导致大鼠脑白质氧化性损伤增加,抗氧化防御能力降低:氧化性损伤的增加和抗氧化防御能力的降低与慢性脑缺血所致的脑白质损伤密切相关.     

额叶皮质损伤对大鼠基底前脑胆碱能神经元的影响

本实验探讨了前额叶皮质局限性损伤对大鼠学习、记忆功能及基底前脑胆碱能神经元的影响。用外科手术造成大鼠一侧前额叶皮质局限性损伤后不同时间、用Ｙ型迷宫检测学习、记忆功能、用组织化学技术检测基底前脑含乙酰胆碱酸酶（ＡChE)活性神经元。实验观察到前额叶皮质损伤后１周,动物学习,记忆功能有所障碍,损伤同侧的基底前脑胆碱能神经元有所减少,但均无统计学意义,损伤后２,３,４周,动物学习、记忆障碍明显,损伤同侧基底前脑胆碱能神经元明显减少（Ｐ＜0.05),且两者变化相平行。结果表明单侧前额叶皮质局限性损伤不仅可引起动物学习、记忆功能障碍,且可引起同侧基底前脑胆碱能神经元丢失,且两者发展相平行,提示基底前脑胆碱能神经元逆行性变性在动物额叶皮质损伤引起的学习、记忆障碍中起作用。     

Effects of dihydroergotoxine on central cholinergic neuronal systems and discrimination learning test in aged rats.

We evaluated changes in the cholinergic neuronal system and learning ability with aging. Choline acetyltransferase (ChAT) activity, a presynaptic index of the cholinergic system, was decreased in the cerebral cortex, hippocampus, striatum, and hypothalamus in the brain of aged rats compared with young adults. Muscarinic cholinergic binding sites (receptors, MCR), a postsynaptic index of the cholinergic system, were markedly decreased in all areas of the brain. However, intraperitoneal injection of 1 mg/kg of dihydroergotoxine (DHET) for 14 days normalized both ChAT and MCR in the cerebral cortex and hippocampus. In the striatum, ChAT was normalized, but MCR did not recover. Aged rats showed marked learning impairment in a 30-day operant type brightness discrimination learning test. Daily DHET administration restored the discrimination ability in the aged rats to nearly the young adult level. DHET had no effects on central cholinergic indices or learning test results in young adult rats. These findings suggest that learning is impaired in aged rats due to impairment in the central cholinergic neuronal system, and that DHET normalizes the decreased function in this system, restoring the learning ability.     

Alterations in the cholinergic system after frontal cortical infarction in rat brain: pharmacological magnetic resonance imaging of muscarinic receptor responsiveness and stereological analysis of cholinergic forebrain neurons

Vascular cognitive impairment has been related to dysfunction of the central cholinergic system. Studies exploring the putative relationship between vascular cognitive impairment and cholinergic dysfunction have largely been aimed at symptomatic cholinergic treatment rather than focusing on etiological and pathological factors. The present study characterizes chronic responses of the cholinergic system to focal cerebral infarction. Two separate experiments investigated changes in receptor responsiveness versus changes in cell number after photothrombotic infarction of the frontal cortex in rat brain. First, we conducted pharmacological magnetic resonance imaging (phMRI) together with pilocarpine injection to assess relative cerebral blood volume (CBV) responses related to cholinergic muscarinic receptor activation. PhMRI was conducted at 1 and 3 weeks after photothrombotic infarction of either the left or right frontal cortex. Second, stereological assessment was performed on choline acetyltransferase (ChAT)-immunostained sections to determine cholinergic cell body count in several basal forebrain nuclei at 4 weeks after infarction. Significant reductions in relative CBV responses were observed both inside the ischemic area at 1 and 3 weeks, and in areas distant from the lesion at 3 weeks after right-sided frontal cortical infarction. In contrast, cholinergic cell number remained unchanged. These results demonstrate that cholinergic receptor responsiveness may be significantly altered following cerebral infarction, while projecting cholinergic cells are preserved.     

Cholinergic deafferentation after focal cerebral infarct in rats

BACKGROUND AND PURPOSE: For a better understanding of neuronal network disturbances after stroke, we investigated the changes in the cholinergic system after experimental focal infarct. METHODS: We quantitatively evaluated the highly sensitive acetylcholinesterase histochemistry and local glucose utilization 7 days after left middle cerebral artery occlusion in Wistar rats. RESULTS: In all rats with occlusion, the ipsilateral frontal cortex and the nucleus basalis Meynert developed no infarct, whereas the subcortical striatum did. In the frontal cortex on the occlusion side, the acetylcholinesterase-positive fiber density was significantly (p less than 0.05) reduced; a computer-assisted image-analyzing system quantified approximately 1.0 m/mm3 brain cortex acetylcholinesterase-positive fibers in the ipsilateral frontal cortex layers II-IV and approximately 9.7 m/mm3 brain cortex acetylcholinesterase-positive fibers in the contralateral frontal cortex layers II-IV. Local glucose utilization was also significantly (p less than 0.05) decreased in the ipsilateral frontal cortex compared to the contralateral side and sham-operated animals. CONCLUSIONS: These results suggest that functional disturbances and disruption of the cholinergic pathway between the frontal cortex and the nucleus basalis Meynert occur after middle cerebral artery occlusion in rats.     

Long-term time course of regional changes in cholinergic indices following transient ischemia in the spontaneously hypertensive rat brain

Using an animal model of forebrain ischemia in spontaneously hypertensive rats (SHR) by 3-h bilateral carotid occlusion, and various indices of the cerebral cholinergic system were assessed for periods up to 24 weeks. The lesions observed histologically in the hippocampus of SHR 2 weeks after ischemia were less severe than those in the frontal cortex. Marked elevation of acetylcholine concentration was transiently observed in the frontal cortex, hippocampus and thalamus + midbrain at 2 weeks, and in the striatum at 1–4 weeks after ischemia. Choline acetyltransferase activity remained unchanged in all regions throughout the experimental period except for a minimal decrease in the frontal cortex at 4 weeks. Choline esterase (ChE) activity was slightly decreased in the frontal cortex at 2–4 weeks after ischemia but recovered by 8 weeks. A decrease in the hippocampus was seen at 8 weeks. The B_max for the M1-receptor was significantly reduced by 2 weeks in the frontal cortex and by 4 weeks in the hippocampus. Low B_max values in both regions persisted through week 24. These delayed hippocampul changes in the ChE activity and M1-receptor in SHR were similar to those of the very much delayed changes in M1-receptor previously reported in the gerbil model for transient ischemia. In contrast, Wistar-Kyoto rats (WKY), used as normotensive controls, exhibited no histological or biochemical changes for up to 24 weeks. The difference between SHR and WKY may depend on the more severe cerebral blood flow depletion during carotid ligation in the former. The chronic state of SHR after the transient ischemia may be a useful pathophysiological model for human cerebral infarctions with hypertension.     

Selective cholinergic denervation of the cingulate cortex impairs the acquisition and performance of a conditional visual discrimination in rats

Results from excitotoxic lesion studies have implicated the cingulate cortex and its basal forebrain afferents in the acquisition and performance of conditional discrimination tasks. In the present work, we sought to clarify the role of specifically cholinergic projections from the vertical limb nucleus of the diagonal band (VDB) to the cingulate cortex in conditional visual discrimination (CVD) learning and performance in rats. We injected the cholinergic immunotoxin 192 IgG-saporin into the cingulate cortex to produce selective retrograde lesions of the cholinergic neurons projecting from the VDB to the cingulate cortex with the aim of sparing afferents of non-cingulate regions that can be disrupted by excitotoxic or immunotoxic VDB injections and non-cholinergic VDB projections that can also be damaged by excitotoxic lesions. Rats sustaining selective cholinergic denervation in this manner were significantly impaired relative to sham-operated animals in the acquisition and performance of a CVD rule of the type 'If lights are flashing FAST, press the left lever; if SLOW, press right'. Asymptotic performance of the lesion group was substantially lower than for control rats, indicating an enduring performance deficit. This impairment was associated with a selective disruption on trials with the FAST flashing stimulus. The results confirm the involvement of cholinergic innervation of the cingulate cortex in CVD performance; however, the nature of the deficit suggests a role for cholinergic modulation in task-relevant stimulus processing rather than stimulus-response learning per se.     

Neurochemical and behavioral recovery after colchicine lesions of the nucleus basalis magnocellularis in rats

Experimentally-induced lesions of the basal forebrain have been used to test the hypothesis that the cholinergic system plays a critical role in learning and memory. In the present study, a basal forebrain infusion of colchicine, a microtubule assembly inhibitor, was used to characterize the relationship between a cholinergic marker and behavioral function. Bilateral infusions were made in the nucleus basalis magnocellularis (NBM) of male Long-Evans rats. At 4 weeks post-lesion, behavioral assessments were made on half of the rats in each group. These rats were sacrificed 1 week later and regional choline acetyltransferase (ChAT) activity was measured. The remaining rats were behaviorally tested 11 weeks post-lesion and sacrificed 12 weeks post-lesion. The brains of additional rats were studied for Nissl-staining, ChAT-, GAD- and metEnk immunoreactivity (IR) and AChE histochemistry. At 5 weeks after colchicine infusion, there was a significant decrease in parietal and frontal cortical ChAT activity, impaired acquisition of a water maze spatial navigation task and decreased passive avoidance cross-over latency. At 12 weeks after colchicine infusion, ChAT activity was decreased in frontal but not parietal cortex; acquisition of the water maze task was not significantly different from vehicle-infused rats, and a significant deficit was observed in passive avoidance latency. ChAT-IR in the NBM showed a significant decrease at both time points, while changes in AChE-stained cortical fibers paralleled the ChAT activity. GAD- and metEnk-IR were decreased but were not different between the two time points. These data show task-specific behavioral recovery associated in time with recovery of regional cholinergic markers.     

Task-dependent memory loss and recovery following unilateral nucleus basalis lesion: behavioral and neurochemical correlation

We found that rats with unilateral AF64A lesions of the nucleus basalis of Meynert (nbM) showed significant impairment of active avoidance and Morris water maze learning. Impairment of active avoidance learning almost subsided within one month but impairment of Morris water maze learning persisted 5 months later. Two weeks after production of the lesion, choline acetyltransferase (ChAT) activity was reduced by 45% in the frontal cortex (FC), but not in the hippocampus or corpus striatum. The decreased ChAT activity in the FC gradually recovered, but it was still reduced by 20% even after 20 weeks. In contrast, ChAT activity on the contralateral side of the FC began to increase from 5 weeks onwards. Histological examination also indicated that loss of cholinergic fibers in the FC gradually recovered with time after induction of the lesion. The results from the present study suggest that specific learning (Morris water maze) tasks involve the cholinergic system and that recovery of cholinergic function (ChAT) may be related to plasticity of the contralateral FC.     

Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment

Chronic cerebral hypoperfusion (CCH) induces cognitive impairment, but the compensative mechanism of cerebral blood flow (CBF) is not fully understood. The present study mainly investigated dynamic changes in CBF, angiogenesis, and cellular pathology in the cortex, the striatum, and the cerebellum, and also studied cognitive impairment of rats induced by bilateral common carotid artery occlusion (BCCAO). Magnetic resonance imaging (MRI) techniques, immunochemistry, and Morris water maze were employed to the study. The CBF of the cortex, striatum, and cerebellum dramatically decreased after right common carotid artery occlusion (RCCAO), and remained lower level at 2 weeks after BCCAO. It returned to the sham level from 3 to 6 weeks companied by the dilation of vertebral arteries after BCCAO. The number of microvessels declined at 2, 3, and 4 weeks but increased at 6 weeks after BCCAO. Neuronal degeneration occurred in the cortex and striatum from 2 to 6 weeks, but the number of glial cells dramatically increased at 4 weeks after BCCAO. Cognitive impairment of ischemic rats was directly related to ischemic duration. Our results suggest that CCH induces a compensative mechanism attempting to maintain optimal CBF to the brain. However, this limited compensation cannot prevent neuronal loss and cognitive impairment after permanent ischemia.     

Amphetamine-induced increase in rat cerebral blood flow: Apparent lack of catecholamine involvement

The influence of D,L-amphetamine (5 mg/kg i.p.) on regional cerebral blood flow (CBF) in rats has been studied after surgically or pharmacologically induced depletion of brain catecholamines. (1) Bilateral removal of the superior cervical ganglion (one week before the experiment) did not prevent the amphetamine-induced augmentation of CBF present in intact animals to 2--4 times above the control value. Maximal changes occurred in the frontal and parietal cortex. (2) Destruction of the ascending noradrenergic pathways by uni- or bilateral injections of 6-hydroxydopamine, which decreased the noradrenaline (NA) level in the frontal cortex by 89%, was ineffective in abolishing the increase in CBF caused by the drug in the frontal cortex. (3) The involvement of other catecholaminergic systems was excluded by pretreatment of the rats with reserpine plus a-methyl-p-tyrosine which reduced the levels of NA, dopamine and adrenaline in the frontal cortex with 92, 97 and 99% respectively. Such treatment did not alter the effect of amphetamine on CBF in the frontal cortex. The results support the hypothesis that the action of amphetamine on CBF is not mainly mediated by catecholamines.     

Differential changes in rat cholinergic parameters subsequent to immunotoxic lesion of the basal forebrain nuclei

The degree of lesion produced by 192 IgG-saporin relative to controls was compared using three independent methods. Microdialyzed acetylcholine (ACh), choline acetyltransferase (ChAT) activity, and the rate of ACh synthesis were compared in the frontal cortex and hippocampus. Microdialysis of rats was performed 1 and 15 weeks post-lesion. In week 16, the rats were sacrificed after an injection of deuterated choline (Ch) for determination of the rate of ACh synthesis. ChAT activity was determined at the same timepoints in a separate set of rats. At 1 week, ChAT activity and microdialyzed ACh showed similar degrees of depletion. At 15 weeks, microdialyzed ACh was significantly lower than the synthesis rate in cortex, but not in hippocampus. A small increase in ChAT activity between 1 and 15 weeks was found in the cortex, but not hippocampus. In the hippocampus, however, the rate of ACh synthesis was significantly greater than ChAT activity. This was true for two doses of immunotoxin; the greater compensation occurring with the lesser lesion. Microdialyzed ACh levels were not different from the other measures in hippocampus. Residual cholinergic terminals in the hippocampus, but not frontal cortex, compensate for a selective cholinergic lesion by increasing the rate of synthesis and may thereby alleviate hippocampus-dependent behavioral deficits.     

Selective lesion of the cholinergic basal forebrain causes a loss of cortical neuropeptide Y and somatostatin neurons

Degeneration of the cholinergic basal forebrain (CBF) and changes in cortical neuropeptide levels have been reported in Alzheimer's disease. In the present study, we sought to determine if a selective cholinergic lesion of nucleus basalis magnocellularis (Nbm) could affect the number and distribution of neuropeptide Y (NPY) and somatostatin (SS) immunoreactive neurons in the frontoparietal and occipital cortices of rats. Brain sections were evaluated at survival times of 1, 2, 4, 8, 12, 24, 48, 78 and 100 weeks after intraventricular injection of 192-saporin, an immunotoxin directed at the low affinity neurotrophin receptor (p75^NGFr), that selectively destroys the CBF. Following the immunotoxin lesion of the Nbm, the number of NPY-labeled neurons decreased 33% in the frontoparietal cortex and 60% in the occipital cortex compared to age-matched normal controls at most survival time points. A significant loss of SS-labeled neurons in both cortical regions was seen 12 weeks after 192-saporin injection with no further change up to 100-week survival time. The effect of age on neuropeptidergic populations was evaluated in normal control rats. The number of NPY and SS immunoreactive neurons in aged rats (21–26 months) decreased by 42% in the frontoparietal cortex and 27% in the occipital cortex when compared with young (3–6 months) and middle-age (9–14 months) rats. When both non-lesioned and lesioned animals with different ages were pooled for linear regression, a significant correlation was found between the number of cortical NPY- and SS-labeled neurons and cortical acetylcholinesterase (AChE) histochemical staining intensity. These findings indicate that: (1) cholinergic denervation of the Nbm is associated with an irreversible loss of neocortical NPY and SS immunoreactive neurons analogous to that observed in Alzheimer's disease and aging; (2) the degree of the loss of cortical NPY and SS immunoreactive neurons seems to be related to the extent of the reduction of cortical AChE intensity in both toxin-injected and normal aged rats. These findings may reflect a trophic dependence of NPY and SS neurons on cortical cholinergic input.     

Aging and stress-induced changes in choline and glutamate uptake in hippocampus and septum of two rat strains differing in longevity and reactivity to stressors

Stress induced changes in neurochemical indices of neurotransmission are more pronounced in the septohippocampal cholinergic system of Wistar Kyoto rats, which are behaviorally more reactive to Stressors and have a shorter life span, than in Brown Norway rats. Moreover, pronounced degeneration of septohippocampal cholinergic neurons occurs earlier in life in Wistar Kyoto rats. In the present study the high affinity synaptosomal uptakes of choline and glutamate were used as indices for cholinergic and glutamatergic systems respectively. Following 2 hr of mild restraint stress increases in both uptake systems were observed in all regions examined (hippocampus, septum and frontal cortex). The stress-induced increases were generally similar in young (3 months) and aged (20 months) rats of both strains. The noted exception was that choline uptake levels, which were reduced in the hippocampus of unhandled aged WKY rats, remained unchanged after stress. The results confirm the involvement of the septohippocampal cholinergic system in the response to acute stress and extend the findings to include the hippocamposeptal glutamatergic system activation as well. It is suggested that in spite of neuronal degeneration during aging, these responses to stress can be maintained by compensatory efforts of neurons that remain intact.     

Behavior alters the uptake of [3h]choline into acetylcholinergic neurons of the nucleus basalis magnocellularis and medial septal area

Behavioral experience changed sodium-dependent high affinity choline uptake (SDHACU) in the hippocampus and frontal cortex. Rats were trained on various behavioral tasks and sacrificed after testing. SDHACU was determined in frontal cortex and hippocampus, areas that receive cholinergic innervation from the nucleus basalis magnocellularis (NBM) and the medial septal area (MSA), respectively. Untrained rats taken directly from their home cages had fairly consistent levels of SDHACU in the hippocampus (1.76 ± 0.45, X ± S.E.) and frontal cortex (1.46 ± 0.37). In the hippocampus of rats performing in a radial maze and T-maze and in rats that surpassed a criterion level in an active avoidance task, SDHACU increased significantly above Cage (untrained) group levels. In the cortex of rats performing the radial maze task, SDHACU decreased slightly. There were no other changes in frontal cortical SDHACU. After behavioral testing ceased, SDHACU in rats performing the radial maze task remained elevated above Control and Treadmill group levels for 20 days, but returned to near control levels 40 days later. Our data demonstrate that a functional differentiation exists between the MSA and NBM cholinergic systems, and that the measurement of SDHACU in central cholinergic neurons is a useful tool to identify the influences of behavior and environment upon changes in neurochemical events and neuronal activity.     

Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: Modification by cholinergic drugs

Five common marmosets (Callithrix jacchus) received unilateral ibotenic acid lesions of the basal nucleus of Meynert (nBM). Seven days later, choline acetyltransferase activity was significantly reduced by 50% in the frontal and temporal neocortex, 40% in the amygdala, and 30% in the motor, parietal and occipital cortex in the ipsilateral hemisphere. Four marmosets receiving equivalent bilateral ibotenic acid lesions were severely impaired on new visual object discrimination learning and on relearning an object discrimination learnt prior to surgery when compared with operated controls. New learning in lesioned animals was substantially improved by i.m. administration of the cholinergic agonist arecoline. Lesioned animals' learning ability improved with time but these animals were then differentially sensitive to the disruptive effect of scopolamine on discrimination learning. These results show that lesions of the nBM which destroy the rising cholinergic pathways impair learning ability but that this ability can be substantially restored by administration of a cholinergic agonist.     

Plastic changes in the cholinergic innervation of the rat cerebral cortex after unilateral lesion of the nucleus basalis with α-amino-3-OH-4-isoxozole propionic acid (AMPA): Effects of basal forebrain transplants into neocortex

Unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced a nearly complete loss of cholinergic markers in the ipsilateral frontal and parietal cortices with no recovery at 6 months. The loss was associated with compensatory increases in AChE-positive fibre density in the contralateral cortex, in ipsilateral cortical regions not receiving their cholinergic innervation from the nbm and in the size of cholinergic magnocellular neurones in the contralateral nbm. The hypertrophy and increase in AChE-positive fibre density were apparent at 4–6 weeks after lesion and increased with time. Cholinergic transplants to cholinergically deafferented cortex prevented development of the compensatory increases in AChE-positive fibre density and restored AChE-positive fibre density and ChAT activity to control levels in ipsilateral cholinergically deafferented regions, partially after 6–8 weeks and completely after 6 months. In contrast, when cholinergic grafts were placed into unlesioned cortex, axonal outgrowth was localized to the vicinity of the transplant and did not develop with time. These results support the concept that vacant synapses promote and direct axonal outgrowth from transplanted neurones and that grafted cholinergic neurones integrate into the lesioned forebrain cholinergic projections system and prevent the lesion-induced changes in AChE-positive fibre density and ChAT activity.     

Glutamate and GABA concentration in the brain and cerebrospinal fluid of rats treated with phosphatidylcholine

Phosphatidylcholine increases CNS concentrations of acetylcholine. In rats we investigated whether or not phosphatidylcholine also influences the neurotransmitters glutamate and GABA. In 17 rats 1.5 gram/kg Lethicon perorally was administered daily for 2 weeks, 15 rats served as controls. In tissue from frontal cortex, striatum, substantia nigra, cerebellar cortex no significant differences between treated and untreated animals were found in glutamate or GABA concentrations. A central nervous interaction between the cholinergic system and the neurotransmitters glutamate and GABA, therefore, could not be demonstrated after 2 weeks of phosphatidylcholine intake.     

Neuroimaging findings in Alzheimer's disease

In the present article, the neuroimaging findings in Alzheimer's disease are summarized and experimental data from animals relating to metabolic changes in Alzheimer's disease (AD), particularly in the frontobasal cholinergic projections onto the cerebral cortex, are reviewed. Changes in glucose metabolism as well as in cerebral blood flow (CBF) are specific for AD, in which the parietotemporal association cortex shows metabolic suppression. This finding is used as a diagnostic aid in the clinical application of single photon emission computed tomography. In rare cases, limited suppression of metabolism and blood flow is also found in the unilateral medial temporal lobe or parietal lobe. Statistically, approximately 80% of cases of AD show a typical parietotemporal suppression pattern of CBF. This cortical metabolic and circulatory suppression has been attributed to cholinergic deprivation from the basal forebrain Mynert nucleus. Animal experiments have revealed transient cortical suppression of glucose metabolism in the frontal cortex after destruction of the basal forebrain cholinergic neurons by ibotenic acid. This suppression persists for approximately 1 week and returns to normal 1 month after operation. Thus, the typical neuroimaging findings in AD would not be due to deficient cholinergic projections from the basal forebrain.     

Neurochemical recovery in the neocortex after colchicine lesions of the nucleus basalis magnocellularis in rats

Neurochemical recovery was investigated in male, Fischer-344 rats up to 3 months after lesions of the nucleus basalis. Bilateral injections of colchicine (1.0 micrograms/site) into the nucleus basalis magnocellularis (NBM) resulted in a 30% decrease in choline acetyltransferase (ChAT) activity in frontal cortex 4 weeks after surgery, compared to unlesioned controls. ChAT activity in the frontal cortex gradually recovered to control levels by 12 weeks. The loss of ChAT-immunoreactive neurons in the NBM observed 4 weeks after surgery was still evident 12 weeks after surgery. These results suggest that surviving cholinergic neurons in the NBM contribute to recovery of ChAT activity in the neocortex.