Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: age, sex and region-specific changes.

Fragile X syndrome is a learning disability caused by excess of CGG repeats in the 5' untranslated region of the Fragile X gene (FMR1) silencing its transcription and translation. We used a murine model of this condition, Fmr1 knock-out mice (KO) to study acetylcholine (ACh) metabolism and compared it to that of wild-type control mice (WT). Brain endogenous ACh (D0ACh), free choline (D0Ch), their deuterated variants D4ACh and D4Ch and mole ratios (AChMR and ChMR) were measured by gas chromatography-mass spectrometry in the cerebral hemisphere, cerebral cortex, hippocampus and cerebellum, following D4Ch administration. Regression analysis indicated a significant decrease with age (negative slope) of D4ACh, AChMR, D4Ch and ChMR in WT mice. Age dependence was only present for D4ACh and AChMR in KO mice. Analysis of variance with age as covariate indicated a significant greater D4Ch in the cerebral cortex of KO females when compared to WT females. Contrasts between sexes within genotypes indicated lower D0Ch in cortex and cerebellum of female KO mice but not in WT and lower D4Ch in hippocampus of female KO and WT mice. In conclusion, after adjusting for age, D0ACh concentrations and synthesis from deuterium-labeled Ch were similar in KO and control WT mice in all brain regions. In contrast, significant changes in Ch dynamics were found in hippocampus and cerebral cortex of KO mice that might contribute to the pathogenesis of FXS.

Flattened cortical maps of cerebral function in the rat: a region-of-interest approach to data sampling, analysis and display.

We describe a method for the measurement, analysis and display of cerebral cortical data obtained from coronal brain sections of the adult rat. In this method, regions-of-interest (ROI) are selected in the cortical mantle in a semiautomated fashion using a radial grid overlay, spaced in 15 degrees intervals from the midline. ROI measurements of intensity are mapped on a flattened two-dimensional surface. Topographic maps of statistical significance at each ROI allow for the rapid viewing of group differences. Cortical z-scores are displayed with the boundaries of brain regions defined according to a standard atlas of the rat brain. This method and accompanying software implementation (Matlab, Labview) allow for compact data display in a variety of autoradiographic and histologic studies of the structure and function of the rat brain.

Cortical contusion induces trans-hemispheric reorganization of blood flow maps.

Cerebral blood flow (CBF), a surrogate of neural activity in the identification of brain regions involved in specific functions, has been used in this report to trace the compensatory enhancement of activity in non-traumatized areas of the brain following a focal lesion. We have previously shown activation of CBF in the cortex contralateral to a focal contusion, 24 h after the event. The present report extends the characterization of this trans-hemispheric cortical blood flow activation by studying its time course and regional distribution from 4 days to 4 weeks post-trauma. Adult male Sprague-Dawley rats received a cortical impact through a 6.3 mm craniotomy under halothane anesthesia. CBF was measured with the quantitative autoradiographic (14)C-Iodoantipyrine technique, in conscious animals, 4 days, 2 weeks and 4 weeks post-trauma. CBF was severely decreased at the site of impact where necrosis developed later, and it remained depressed in the surrounding areas throughout the observation period. Trans-hemispheric CBF enhancement was maximal at 4 days and it returned to control levels 28 days post-trauma. This phenomenon was present in all cortical regions symmetrical to the impact zone, but also in auditory, visual, entorhinal and insular cortex. These results suggest that the participation of the contralateral cortex in the recovery from unilateral brain trauma is not limited to the regions homologous to those that received the impact. The time course of CBF changes was found to be consistent with the recovery of motor function in this model.

Activation of cerebral cortex during acoustic challenge or acute foot-shock in freely moving, nontethered rats.

Most brain mapping techniques require immobilization of the subject, which extinguishes all but the simplest behaviors. We applied in freely moving rats an implantable microbolus infusion pump (MIP) which can be triggered by remote activation for the injection of the cerebral blood flow tracer [(14)C]iodoantipyrine during behavioral activation. Consistent with previous electrophysiological, metabolic and brain anatomic studies, CBF-related tissue radioactivity (CBF-TR) increased in acoustic cortex during a 1000 Hz/8000 Hz alternating tone. In response to an acute foot-shock, CBF-TR increased in visual cortex, parietal association cortex, and extended into primary motor cortex, and primary somatosensory cortex mapping the trunk. These results support the utility of implantable pumps as adjunct tools for studying cerebral activation during behavioral challenges in nontethered, nonrestrained animals.

Functional brain mapping in freely moving rats during treadmill walking.

A dilemma in functional neuroimaging is that immobilization of the subject, necessary to avoid movement artifact, extinguishes all but the simplest behaviors. Recently, we developed an implantable microbolus infusion pump (MIP) that allows bolus injection of radiotracers by remote activation in freely moving, nontethered animals. The MIP is examined as a tool for brain mapping in rats during a locomotor task. Cerebral blood flow-related tissue radioactivity (CBF-TR) was measured using [14C]-iodoantipyrine with an indicator-fractionation method, followed by autoradiography. Rats exposed to walking on a treadmill, compared to quiescent controls, showed increases in CBF-TR in motor circuits (primary motor cortex, dorsolateral striatum, ventrolateral thalamus, midline cerebellum, copula pyramis, paramedian lobule), in primary somatosensory cortex mapping the forelimbs, hindlimbs and trunk, as well as in secondary visual cortex. These results support the use of implantable pumps as adjunct tools for functional neuroimaging of behaviors that cannot be elicited in restrained or tethered animals.

An implantable bolus infusion pump for use in freely moving, nontethered rats.

One of the current constraints on functional neuroimaging in animals is that to avoid movement artifacts during data acquisition, subjects need to be immobilized, sedated, or anesthetized. Such measures limit the behaviors that can be examined, and introduce the additional variables of stress or anesthetic agents that may confound meaningful interpretation. This study provides a description of the design and characteristics of a self-contained, implantable microbolus infusion pump (MIP) that allows triggering of a bolus injection at a distance in conscious, behaving rats that are not restrained or tethered. The MIP is externally triggered by a pulse of infrared light and allows in vivo bolus drug delivery. We describe application of this technology to the intravenous bolus delivery of iodo[(14)C]antipyrine in a freely moving animal, followed immediately by lethal injection, rapid removal of the brain, and analysis of regional cerebral blood flow tissue radioactivity with the use of autoradiography. The ability to investigate changes in brain activation in nonrestrained animals makes the MIP a powerful tool for evaluation of complex behaviors.

Heart rate dynamics in monoamine oxidase-A- and -B-deficient mice.

Heart rate (HR) dynamics were investigated in mice deficient in monoamine oxidase A and B, whose phenotype includes elevated tissue levels of norepinephrine, serotonin, dopamine, and phenylethylamine. In their home cages, spectral analysis of R-R intervals revealed more pronounced fluctuations at all frequencies in the mutants compared with wild-type controls, with a particular enhancement at 1-4 Hz. No significant genotypic differences in HR variability (HRV) or entropies calculated from Poincaré plots of the R-R intervals were noted. During exposure to the stress of a novel environment, HR increased and HRV decreased in both genotypes. However, mutants, unlike controls, demonstrated a rapid return to baseline HR during the 10-min exposure. Such modulation may result from an enhanced vagal tone, as suggested by the observation that mutants responded to cholinergic blockade with a decrease in HRV and a prolonged tachycardia greater than controls. Monoamine oxidase-deficient mice may represent a useful experimental model for studying compensatory mechanisms responsible for changes in HR dynamics in chronic states of high sympathetic tone.

Increased baroreceptor response in mice deficient in monoamine oxidase A and B.

The recent development of mice doubly deficient for monoamine oxidase A and B (MAO-A/B, respectively) has raised questions about the impact of these mutations on cardiovascular function, in so far as these animals demonstrate increased tissue levels of the vasoactive amines serotonin, norepinephrine, dopamine, and phenylethylamine. We recorded femoral arterial pressures and electrocardiograms in adult MAO-A/B-deficient mice during halothane-nitrous oxide anesthesia as well as 30 min postoperatively. During both anesthesia and recovery, systolic, diastolic, and mean arterial pressures were 10-15 mmHg lower in MAO-A/B-deficient mice compared with normal controls (P < 0.01). Mutants also showed a greater baroreceptor-mediated reduction in heart rate in response to hypertension after intravenous pulses of phenylephrine or angiotensin II. Tachycardia elicited in response to hypotension after nitroprusside was greater in mutants than in controls. Heart rate responsiveness to changes in arterial pressure was abolished after administration of glycopyrrolate, with no differences in this phenomenon noted between genotypes. These data suggest that prevention of hypertension may occur in chronic states of catecholaminergic/indoleaminergic excess by increased gain of the baroreflex.

Regional cerebral cortical activation in monoamine oxidase A-deficient mice: differential effects of chronic versus acute elevations in serotonin and norepinephrine.

Mice deficient in monoamine oxidase A have previously been shown to demonstrate a chronic elevation of serotonin and norepinephrine in the brain. Using the autoradiographic [14C]iodo-antipyrine method, we examined cerebral cortical blood flow in conscious, restrained four- to five-month-old knock-out and wild-type animals following the intraperitoneal administration of either saline or D-fenfluramine. Knock-out animals administered saline, compared to their wild-type counterparts, demonstrated a significantly higher regional cortical blood flow in somatosensory and barrel field neocortex, an area which previous histological studies have shown to be characterized by abnormal serotonergic projection fibers and absent barrel formation. Regional cortical blood flow was significantly lower in knock-out than in wild-type mice in the entorhinal and midline motor cortex, with non-significant decreases noted in the olfactory, piriform and retrosplenial cortices and the amygdala. We compared the above findings to those obtained in response to D-fenfluramine which, in conjunction with its metabolite D-norfenfluramine, results in acute elevations of brain levels of serotonin and norepinephrine. Administration of D-fenfluramine (21. 2mg/kg) resulted in changes in regional cortical perfusion in most brain regions of both knock-out and wild-type mice that were opposite to the genotypic differences seen in perfusion in response to saline. Fenfluramine significantly increased regional cortical blood flow in the allocortex (olfactory, piriform, entorhinal) and the amygdala, and significantly decreased regional cortical blood flow in the somatosensory, barrel field, midline motor and retrosplenial cortices. Changes in regional perfusion in response to fenfluramine were topographically equivalent in knock-out and wild-type mice, although in knock-out mice such changes were of greater magnitude. Our study suggests that the effects on regional cortical blood flow of a lifelong absence of monoamine oxidase A, and the consequent chronic increase in serotonin and norepinephrine, differ from those attributable to acute increases in these neurotransmitters following fenfluramine administration. Such a differential response may reflect neurodevelopmental abnormalities and/or effects of a chronic physiological adaptation on the regulation of cortical activation.

Hypertension in beta-adducin-deficient mice.

Polymorphic variants of the cytoskeletal protein adducin have been associated with hypertension in humans and rats. However, the direct role of this protein in modulating arterial blood pressure has never been demonstrated. To assess the effect of beta-adducin on blood pressure, a beta-adducin-deficient mouse strain (-/-) was studied and compared with wild-type controls (+/+). Aortic blood pressure was measured in nonanesthetized, freely moving animals with the use of telemetry implants. It is important to note that these mice have at least 98% of C57Bl/6 genetic background, with the only difference from wild-type animals being the beta-adducin mutation. We found statistically significant higher levels of systolic blood pressure (mm Hg) (mean+/-SE values: -/-: 126.94+/-1.14, n=5; +/+: 108.06+/-2. 34, n=6; P:

Increasing muscle mass in spinal cord injured persons with a functional electrical stimulation exercise program.

OBJECTIVE: To determine the magnitude of changes in muscle mass and lower extremity body composition that could be induced with a regular regimen of functional electrical stimulation (FES)-induced lower-extremity cycling, as well as the distribution of changes in muscle mass among the thigh muscles in persons with spinal cord injury (SCI). STUDY DESIGN: Thirteen men with neurologically complete motor sensory SCI underwent a 3-phase, FES-induced, ergometry exercise program: phase 1, quadriceps strengthening: phase 2, progressive sequential stimulation to achieve a rhythmic pedaling motion (surface electrodes placed over the quadriceps, hamstrings, and gluteal muscles); phase 3, FES-induced cycling for 30 minutes. Participants moved from one phase to the next when they met the objectives for the current phase. MEASURES: Computed tomography of legs to assess muscle cross-sectional area and proportion of muscle and adipose tissue. Scans were done at baseline (before subjects started the program), at first follow-up, typically after 65.4+/-5.6 (SD) weekly sessions, and at second follow-up, typically after 98.1+/-9.1 sessions. RESULTS: Increases in cross-sectional areas were found in the following muscles: rectus femoris (31%, p<.001). sartorius (22%, p<.025), adductor magnus-hamstrings (26%, p<.001), vastus lateralis (39%, p = .001), vastus medialis-intermedius (31%, p = .025). Cross-sectional area of adductor longus and gracilis muscles did not change. The ratio of muscle to adipose tissue increased significantly in thighs and calves. There was no correlation among the total number of exercise sessions and the magnitude of muscle hypertrophy. CONCLUSIONS: Muscle cross-sectional area and the muscle to adipose tissue ratio of the lower extremities increased during a regular regimen of 2.3 FES-induced lower extremity cycling sessions weekly. The distribution of changes was related to the proximity of muscles to the stimulating electrodes.

Lack of protection of monoamine oxidase B-deficient mice from age-related spatial learning deficits in the Morris water maze.

Monoamine oxidase B (MAO-B) increases in brain in response to aging and neurodegeneration. Whether such increases represent a risk factor to further neuronal damage or simply represent epiphenomena remains unclear. L-deprenyl, an inhibitor of MAO-B, has been shown to improve learning in aged rodents. However, recent data suggests this may occur through mechanisms independent of its enzymatic inhibition. This study investigates visualspatial learning of MAO-B deficient mice and examines what effects absence of MAO-B has on age-related cognitive decline. Learning was tested in the Morris Water Maze in male transgenic MAO-B knockout mice (KO) ages 2 months (n = 9), 7 months (n = 7), and 17 months (n = 8). Performance was compared to that of wild type (WT) littermates. Animals were given four 60 second trials per day with the submerged platform in the "North" position. Animals received 7 days of learning in which they were introduced into the pool facing the wall, alternating between the "East" and "West" positions. A single probe trial followed on day 8, followed by continuation of the original learning paradigm on days 9 and 10. Subsequently, the platform position was changed to the diagonally opposite quadrant and learning continued on days 11-13, followed by a cue phase in which the platform was made visible. Total distance traveled and latency to the platform was increased in 7- and 17- month old mice, most significantly at the beginning of the acquisition phase. This effect reappeared again in 17- month old mice during the reversal phase. No predominant genotypic differences in latency or distance were observed during any phase of the experiment. Our results show that presence or absence of MAO-B does not appear to alter performance in the Morris water maze. Furthermore, presence or absence of MAO-B does not provide protection from the age-dependent deficits in spatial learning.

Changes in electrocortical power and coherence in response to the selective cholinergic immunotoxin 192 IgG-saporin.

Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 microg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%-84%) and hippocampus (93%), with relative sparing of entorhinal-piriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1- to 4-Hz power, decreases in 20- to 44-Hz power, and decreases in 4- to 8-Hz intra- and interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial cholinergic reserve remains following administration of 192 IgG-saporin, despite dramatic losses of ChAT in cortex and hippocampus. Persistence of a cholinergically modulated RSA suggests that such activity may be mediated through cholinergic neurons which, because they lack the p75 receptor, remain unaffected by the immunotoxin.

Cerebral cortical blood flow maps are reorganized in MAOB-deficient mice.

Cerebral cortical blood flow (CBF) was measured autoradiographically in conscious mice without the monoamine oxidase B (MAOB) gene (KO, n=11) and the corresponding wild-type animals (WILD, n=11). Subgroups of animals of each genotype received a continuous intravenous infusion over 30 min of phenylethylamine (PEA), an endogenous substrate of MAOB, (8 nmol g-1 min-1 in normal saline at a volume rate of 0.11 microl g-1 min-1) or saline at the same volume rate. Maps of relative CBF distribution showed predominance of midline motor and sensory area CBF in KO mice over WILD mice that received saline. PEA enhanced CBF in lateral frontal and piriform cortex in both KO and WILD mice. These changes may reflect a differential activation due to chronic and acute PEA elevations on motor and olfactory function, as well as on the anxiogenic effects of this amine. In addition to its effects on regional CBF distribution, PEA decreased CBF globally in KO mice (range -31% to -41% decrease from control levels) with a lesser effect in WILD mice. It is concluded that MAOB may normally regulate CBF distribution and its response to blood PEA.

Lack of protection from ischemic injury of monoamine oxidase B-deficient mice following middle cerebral artery occlusion.

Adult male wild-type mice received intraperitoneal (i.p.) administration of saline (n = 9) or 10 mg/kg L-deprenyl (n = 9) three times a week for 3 weeks. Mice with targeted inactivation of the monoamine oxidase B (MAO-B) gene received i.p. administration of saline (n = 8). Animals underwent ligation of the left common and external carotid arteries, followed by cauterization of the ipsilateral middle cerebral artery. Twenty-four hours post-surgery, all groups showed right torsion of the torso but no evidence of limb weakness, lateral instability, or circling. Ischemic changes were assessed from digitized video-images of serial sections of the brain stained with Hematoxylin/Eosin. No significant group differences were detected in infarct volume (14-18% of ipsilateral cortex) or in the extent of brain edema (4-7% increase in ipsilateral hemispheric swelling with respect to contralateral side). Our results suggest that absence of the MAO-B gene or inhibition of the enzyme with L-deprenyl are not protective or detrimental in an animal model of acute cortical infarction.

Selective immunotoxin-induced cholinergic deafferentation alters blood flow distribution in the cerebral cortex.

Adult rats received intracerebroventricular (i.c.v.) administration of either phosphate buffer (PBS) or 192 IgG-saporin (Toxin), 3.6 micrograms rat-1, a cholinergic immunotoxin. Six to eight weeks later, the animals received a continuous intravenous (i.v.) infusion of either physostigmine (4.2 micrograms kg-1 min-1) or saline, followed by measurement of cerebral cortical blood flow (CBF) with the autoradiographic Iodo-14C-antipyrine methodology in four groups of animals: Toxin i.c.v.+saline i.v. (n=9), Toxin i.c.v.+physostigmine i.v. (n=6), PBS i.c.v.+saline i.v. (n=6) and PBS i.c.v. +physostigmine i.v. (n=6). Choline acetyltransferase activity (ChAT) was assessed with Fonnum's method in samples of cortical tissue adjacent to the sites of CBF measurement. ChAT decreased in all regions of the Toxin groups when compared to PBS (% decrease: hippocampus=93%, neocortex=80-84%, entorhinal-piriform cortex=42%, amygdala=28%). CBF decreased globally in Toxin+SAL, most severely in posterior parietal and temporal regions (24-40% decrease from PBS+saline). Physostigmine enhanced CBF predominantly in these same areas both in PBS and Toxin animals although to a lesser extent in the latter. Our results demonstrate the importance of cholinergic mechanisms in the control of CBF. The similarity between the topography of CBF decrease following administration of the immunotoxin to that observed in Alzheimer's disease suggests that the CBF pattern observed in this disease may be the result of cholinergic deafferentation.

Functional electrical stimulation effect on skeletal muscle blood flow measured with H2(15)O positron emission tomography.

OBJECTIVE: To test the hypothesis that the limitation in muscle power development with functional electrical stimulation (FES) results from an insufficient increase in muscle blood flow (MBF) in response to activity. SUBJECTS AND METHODS: Five subjects with neurologically complete spinal cord injury (SCI) were tested to measure the MBF response to FES-induced knee extension. The MBF response to voluntary knee extension was measured in five age-matched, able-bodied controls. MBF was measured with positron emission tomography (PET) using H2(15)O as a tracer. Three scans were performed with muscle at rest (baseline), immediately after 16min of FES-induced or voluntary knee extension (activity), and 20min after the second scan (recovery). RESULTS: In SCI subjects, mean +/-SE MBF (mL/100g/min) values were: baseline = 1.85 +/- .48; post-FES = 31.9 +/- 5.65 (p = .0058 vs baseline); recovery = 6.06 +/- 1.52 (p = .0027 vs baseline). In able-bodied controls, mean +/-SE MBF values were: baseline = 8.52 +/- 3.24, post-voluntary exercise = 12.62 +/- 3.03 (p = .023 vs post-FES in SCI subjects); recovery = 10.7 +/- 6.01. CONCLUSIONS: MBF does not appear to be the limiting factor in muscle power generation with FES. The greater increase in MBF observed with FES in SCI subjects when compared with able-bodied subjects performing a similar task (unloaded knee extension against gravity) may relate to abnormal metabolism in FES-stimulated muscle.

Potassium channels participate in gastric mucosal protection in rats with partial portal vein ligation.

Glybenclamide, an adenosine triphosphate-dependent potassium (K+(ATP)) channel blocker, lowered portal pressure and attenuated the hyperdynamic splanchnic circulation in rats with partial portal vein ligation (PPVL). The purpose of this report was to confirm these observations and to test the hypothesis that glybenclamide could reduce acidified ethanol-induced gastric mucosal injury in rats with PPVL. Gastric mucosal blood flow (hydrogen gas clearance), systemic blood pressure, and portal pressure were monitored in rats with PPVL or sham operation (SO). Intravenous glybenclamide (20 mg/kg) or vehicle was administered, followed by intragastric acidified ethanol (0.15 N HCl and 15% ethanol). The area of gastric mucosal lesions was assessed by image analysis. In contrast to published findings, there was no significant elevation of portal pressure after glybenclamide administration in rats with PPVL. Glybenclamide did not alter the gastric mucosal hyperemia in these rats. Glybenclamide significantly increased mucosal injury. The data are consistent with the hypothesis that K+(ATP) channels play a role in protecting the gastric mucosa in rats with PPVL.

Effects of ovariectomy on cerebral flow of rats.

Recent reports suggest that estrogens may enhance cognitive function in postmenopausal women and women suffering from dementia of the Alzheimer's type. One of several proposed mechanisms of action of estrogen has been an improvement in cerebral blood flow (CBF). The current study examined the effects of estrogen deprivation resulting from ovariectomy on the CBF of rats using the quantitative autoradiographic 14C-iodoantipyrine technique. CBF was assessed in passively restrained, awake adult rats at 6 weeks following ovariectomy (n = 10) or sham surgery (n = 10). Rats demonstrated marked endometrial atrophy and a decrease in uterine weight (mean 78%) in response to ovariectomy. Ovariectomized animals did not differ from control animals both in the magnitude and the topography of cortical or subcortical CBF, including the medial preoptic area, amygdala, arcuate nucleus and anterior hypothalamus, areas previously associated with high estrogen binding. These results suggest that in young, surgically ovariectomized animals, hormonal factors do not significantly contribute to changes in basal CBF.

Effects of cholinergic deafferentation and NGF on brain electrical coherence.

Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with nerve growth factor (NGF) or vehicle. Electrocortical coherence was assessed at postoperative days 4, 7, 14, and 21 from all possible pairs of eight epidural electrodes in the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta-1 (12-20 Hz), and beta-2 (20-28 Hz) bands. On day 21 choline acetyltransferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in losses of interhemispheric, as well as bilateral intrahemispheric coherence in the theta band (F1,21 = 28.61, p < 0.0001, F1,21 = 4.30, p < 0.05), with no significant differences seen in other bands. Changes were accentuated during immobility compared with walking and exploratory behavior. Intrahemispheric changes were greatest within the lesioned hemisphere (F1,21 = 6.97, p < 0.01) in long connections between electrode pairings connecting frontal to posterior brain regions. Nerve growth factor (NGF) attenuated losses in ChAT (F1,21 = 21.31, p < 0.0001) and intrahemispheric coherence (F1,21 = 9.66, p < 0.005), whereas interhemispheric coherence showed no significant response. Intact animals receiving NGF showed increases in intrahemispheric coherence, as well as modest increases in ChAT. Increases in coherence in response to NGF occurred within 4-7 days following brain lesions, with no significant change during the 2 weeks thereafter. Our results suggest that coherence is sensitive to cholinergic deafferentation, particularly of long corticocortical connections. NGF differentially restores coherence within hemispheres, as opposed to between hemispheres. Our study suggests that brain function in Alzheimer's disease related to damage of transcallosal fiber tracts may not be responsive to cholinergic treatments. Future studies may wish to evaluate the cognitive relevance of NGF's effects on intact brain.