Brain maps on the go: functional imaging during motor challenge in animals.

Brain mapping in the freely moving animal is useful for studying motor circuits, not only because it avoids the potential confound of sedation or restraints, but because activated brain states may serve to accentuate differences that only manifest partially while a subject is in the resting state. Perfusion or metabolic mapping using autoradiography allows one to examine changes in brain function at the circuit level across the entire brain with a spatial resolution (approximately 100 micro) appropriate for the rat or mouse brain, and a temporal resolution (seconds-minutes) sufficient for capturing acute brain changes. Here we summarize the application of these methods to the functional brain mapping of behaviors involving locomotion of small animals, methods for the three-dimensional reconstruction of the brain from autoradiographic sections, voxel based analysis of the whole brain, and generation of maps of the flattened rat cortex. Application of these methods in animal models promises utility in improving our understanding of motor function in the normal brain, and of the effects of neuropathology and treatment interventions such as exercise have on the reorganization of motor circuits.

Cerebral perfusion mapping during retrieval of spatial memory in rats.

Studies of brain functional activation during spatial navigation using electrophysiology and immediate-early gene responses have typically targeted a limited number of brain regions. Our study provides the first whole brain analysis of cerebral activation during retrieval of spatial memory in the freely-moving rat. Rats (LEARNERS) were trained in the Barnes maze, an allocentric spatial navigation task, while CONTROLS received passive exposure. After 19 days, functional brain mapping was performed during recall by bolus intravenous injection of [14C]-iodoantipyrine using a novel subcutaneous minipump triggered by remote activation. Regional cerebral blood flow (rCBF)-related tissue radioactivity was analyzed by statistical parametric mapping from autoradiographic images of the three-dimensionally reconstructed brains. Functional connectivity was examined between regions of the spatial navigation circuit through interregional correlation analysis. Significant rCBF increases were noted in LEARNERS compared to CONTROLS broadly across the spatial navigation circuit, including the hippocampus (anterior dorsal CA1, posterior ventral CA1-3), subiculum, thalamus, striatum, medial septum, cerebral cortex, with decreases noted in the mammillary nucleus, amygdala and insula. LEARNERS showed a significantly greater positive correlation of rCBF of the ventral hippocampus with retrosplenial, lateral orbital, parietal and primary visual cortex, and a significantly more negative correlation with the mammillary nucleus, amygdala, posterior entorhinal cortex, and anterior thalamic nucleus. The complex sensory component of the spatial navigation task was underscored by broad activation across visual, somatosensory, olfactory, auditory and vestibular circuits which was enhanced in LEARNERS. Brain mapping facilitated by an implantable minipump represents a powerful tool for evaluation of mammalian behaviors dependent on locomotion.

Changes in regional brain perfusion during functional brain activation: comparison of [(64)Cu]-PTSM with [(14)C]-Iodoantipyrine.

A dilemma in behavioral brain mapping is that conventional techniques immobilize the subject, extinguishing all but the simplest behaviors. This is avoided if brain activation is imaged after completion of the behavior and tissue capture of the tracer. A single-pass flow tracer proposed for positron emission tomography (PET) is a radiolabeled copper(II) complex of pyruvaldehyde bis(N(4)-methylthiosemicarbazone), [Cu(64)]-PTSM. [Cu(64)]-PTSM reaches steady-state cerebral distribution more rapidly than the metabolic tracer [(18)F]-fluorodeoxyglucose, allowing imaging with substantially greater temporal resolution. Using dual-label autoradiography, this study compares the relative regional cerebral blood flow tracer distribution (CBF-TR) of [(64)Cu]-PTSM to that of the classic perfusion tracer [(14)C]-iodoantipyrine in a rat model during treadmill walking. Rats were exposed to continuous walking on a treadmill and compared to quiescent controls. [(64)Cu]-PTSM was bolus injected (iv) after 1 min, followed by a 5-minute uptake and subsequent bolus injection of [(14)C]-iodoantipyrine. CBF-TR was quantified by autoradiography and analyzed in the three-dimensionally reconstructed brain by statistical parametric mapping, as well as by region-of-interest analysis. A high homology was found between the [(64)Cu]-PTSM and [(14)C]-iodoantipyrine patterns of cerebral activation in cortical and subcortical regions. For white matter, however, [(64)Cu]-PTSM showed lower perfusion than [(14)Cu]-iodoantipyrine. [(64)Cu]-PTSM is a useful tracer for functional brain mapping in freely-moving subjects. Its application in conjunction with PET promises to increase our understanding of the neural circuitry of behaviors dependent on locomotion.

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.

Reorganization of functional brain maps after exercise training: Importance of cerebellar-thalamic-cortical pathway.

Exercise training (ET) causes functional and morphologic changes in normal and injured brain. While studies have examined effects of short-term (same day) training on functional brain activation, less work has evaluated effects of long-term training, in particular treadmill running. An improved understanding is relevant as changes in neural reorganization typically require days to weeks, and treadmill training is a component of many neurorehabilitation programs. Adult, male rats (n=10) trained to run for 40 min/day, 5 days/week on a Rotarod treadmill at 11.5 cm/s, while control animals (n=10) walked for 1 min/day at 1.2 cm/s. Six weeks later, [(14)C]-iodoantipyrine was injected intravenously during treadmill walking. Regional cerebral blood flow-related tissue radioactivity was quantified by autoradiography and analyzed in the three-dimensionally reconstructed brain by statistical parametric mapping. Exercised compared to nonexercised rats demonstrated increased influence of the cerebellar-thalamic-cortical (CbTC) circuit, with relative increases in perfusion in deep cerebellar nuclei (medial, interposed, lateral), thalamus (ventrolateral, midline, intralaminar), and paravermis, but with decreases in the vermis. In the basal ganglia-thalamic-cortical circuit, significant decreases were noted in sensorimotor cortex and striatum, with associated increases in the globus pallidus. Additional significant changes were noted in the ventral pallidum, superior colliculus, dentate gyrus (increases), and red nucleus (decreases). Following ET, the new dynamic equilibrium of the brain is characterized by increases in the efficiency of neural processing (sensorimotor cortex, striatum, vermis) and an increased influence of the CbTC circuit. Cerebral regions demonstrating changes in neural activation may point to alternate circuits, which may be mobilized during neurorehabilitation.

Early life stress elicits visceral hyperalgesia and functional reorganization of pain circuits in adult rats.

Early life stress (ELS) is a risk factor for developing functional gastrointestinal disorders, and has been proposed to be related to a central amplification of sensory input and resultant visceral hyperalgesia. We sought to characterize ELS-related changes in functional brain responses during acute noxious visceral stimulation. Neonatal rats (males/females) were exposed to limited bedding (ELS) or standard bedding (controls) on postnatal days 2-9. Age 10-11 weeks, animals were implanted with venous cannulas and transmitters for abdominal electromyography (EMG). Cerebral blood flow (rCBF) was mapped during colorectal distension (CRD) using [14C]-iodoantipyrine autoradiography, and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping and functional connectivity. EMG responses to CRD were increased after ELS, with no evidence of a sex difference. ELS rats compared to controls showed a greater significant positive correlation of EMG with amygdalar rCBF. Factorial analysis revealed a significant main effect of 'ELS' on functional activation of nodes within the pain pathway (somatosensory, insular, cingulate and prefrontal cortices, locus coeruleus/lateral parabrachial n. [LC/LPB], periaqueductal gray, sensory thalamus), as well as in the amygdala, hippocampus and hypothalamus. In addition, ELS resulted in an increase in the number of significant functional connections (i.e. degree centrality) between regions within the pain circuit, including the amygdala, LC/LPB, insula, anterior ventral cingulate, posterior cingulate (retrosplenium), and stria terminalis, with decreases noted in the sensory thalamus and the hippocampus. Sex differences in rCBF were less broadly expressed, with significant differences noted at the level of the cortex, amygdala, dorsal hippocampus, raphe, sensory thalamus, and caudate-putamen. ELS showed a sexually dimorphic effect ('Sex x ELS' interaction) at the LC/LPB complex, globus pallidus, hypothalamus, raphe, septum, caudate-putamen and cerebellum. Our results suggest that ELS alters functional activation of the thalamo-cortico-amydala pathway, as well as the emotional-arousal network (amygdala, locus coeruleus), with evidence that ELS may additionally show sexually dimorphic effects on brain function.

Prone positioning decreases cardiac output and increases systemic vascular resistance in neonates.

OBJECTIVE: To evaluate the cardiovascular response to short-term prone positioning in neonates. STUDY DESIGN: In this prospective study, we continuously monitored heart rate (HR), stroke volume (SV) and cardiac output (CO) by electrical velocimetry in hemodynamically stable neonates in each of the following positions for 10 min: supine, prone and back-to-supine position. Skin blood flow (SBF) was also continuously assessed on the forehead or foot using Laser Doppler technology. Systemic vascular resistance (SVR) index was calculated as mean blood pressure (BP)/CO. Data were analyzed using repeated measures analysis of variance. RESULTS: Thirty neonates (gestational age: 35±4 weeks; postmenstrual age: 36±3 weeks) were enrolled. HR did not change in response to positioning. However, in prone position, SV, CO and SBF decreased and SVR index increased from 1.5±0.3 to 1.3±0.3 ml kg(-1) (mean ±s.d., P<0.01), 206±44 to 180±41 ml kg(-1) min(-1) (P<0.01), 0.54±0.30 to 0.44±0.29 perfusion units (P<0.01) and 0.25±0.06 to 0.30±0.07 mm Hg ml(-1) kg(-1) min(-1) (P<0.01), respectively. After placing the infants back-to-supine position, SV, CO, SBF and SVR index returned to baseline. The above pattern of cardiovascular changes was consistent in vast majority of the studied neonates. CONCLUSIONS: Short-term prone positioning is associated with decreased SV, CO and SBF and increased calculated SVR index.

The Effects of Exercise on Dopamine Neurotransmission in Parkinson's Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry.

Animal studies have been instrumental in providing evidence for exercise-induced neuroplasticity of corticostriatal circuits that are profoundly affected in Parkinson's disease. Exercise has been implicated in modulating dopamine and glutamate neurotransmission, altering synaptogenesis, and increasing cerebral blood flow. In addition, recent evidence supports that the type of exercise may have regional effects on brain circuitry, with skilled exercise differentially affecting frontal-striatal related circuits to a greater degree than pure aerobic exercise. Neuroplasticity in models of dopamine depletion will be reviewed with a focus on the influence of exercise on the dorsal lateral striatum and prefrontal related circuitry underlying motor and cognitive impairment in PD. Although clearly more research is needed to address major gaps in our knowledge, we hypothesize that the potential effects of exercise on inducing neuroplasticity in a circuit specific manner may occur through synergistic mechanisms that include the coupling of an increasing neuronal metabolic demand and increased blood flow. Elucidation of these mechanisms may provide important new targets for facilitating brain repair and modifying the course of disease in PD.

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.

Loss of high-frequency brain electrical response to thiopental administration in Alzheimer's-type dementia.

Abnormal brain regions generate proportionately less high-frequency (beta) activity than nonpathological regions, a phenomenon accentuated by barbiturate administration. Using quantitative electroencephalography we examined power in the 20- to 28-Hz band in patients with dementia of the Alzheimer's type (DAT), vascular dementia (VaD), and normal elderly controls (CON) following an IV bolus of thiopental (0.5 mg/kg). Compared to both CON and VaD subjects, DAT subjects showed a marked loss of beta power elicited across the cortex, with largest differences noted in the frontal region. Losses were most significant for the peak response recorded at 30 to 90 s postinjection and persisted during the 5-minute follow-up period. We hypothesize that differences in this electrocerebral response reflect differences in the underlying neuropathology of DAT and VaD subjects. A thiopental challenge may be well suited for the in vivo assessment of brain function in dementias characterized by prominent cortical pathology.

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.

Attenuation of brain high frequency electrocortical response after thiopental in early stages of Alzheimer's dementia.

RATIONALE: Pathological brain regions generate proportionately less high-frequency (beta) activity than non-pathological regions, a phenomenon accentuated by barbiturate administration. OBJECTIVES: Previously, we reported a loss of high-frequency brain electrical response to thiopental in dementia of the Alzheimer's type (DAT). The current study examines whether this phenomenon may be detected in early stages of the illness. METHODS: Using quantitative electroencephalography, we examined power in the 20-28 Hz band in patients with early DAT (n=7, age 71.0+/-3.2 years, Folstein Mini Mental State Score, MMSE 26.2+/-0.8), normal controls (n=8, age 74.3+/-3.2 years, MMSE 29.0+/-0.3) and subjects with moderately severe DAT (n=6, age 76.6+/-3.0 years, MMSE=12.5+/-3.7) at baseline and following an intravenous bolus of thiopental (0.5 mg/kg). RESULTS: No significant group differences in beta power were detectable at baseline. In response to thiopental, early DAT subjects compared to controls showed a significantly smaller beta power response in the frontal region at 1-3 min postinjection. Losses were smaller than those of subjects with moderately severe DAT and demonstrated a non-linear correlation with decreases in cognitive function as assessed by the MMSE score (r2=0.75). CONCLUSION: In early stages of DAT, a barbiturate challenge may unmask abnormalities in brain electrical activity not seen at baseline. Such changes may reflect underlying cortical deafferentation.

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.

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 (delta) power and decreases in high-frequency (beta 2) 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 beta 2-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.

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.

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.

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.

Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B.

The availability of mutant mice that lack either MAO A or MAO B has created unique profiles in the central and peripheral availability of serotonin, norepinephrine, dopamine, and phenylethylamine. This paper summarizes some of the current known phenotypic findings in MAO A knock-out mice and contrast these with those of MAO B knock-out mice. Differences are discussed in relation to the biochemical, behavioral, and physiologic changes investigated to date, as well as the role played by redundancy mechanisms, adaptational responses, and alterations in neurodevelopment.

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.

Tissue-specific effects of estrogen on monoamine oxidase A and B in the rat.

Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. Adult female rats were ovariectomized and randomized to receive a subcutaneous, slow-release preparation of either placebo or one of three doses of 17-beta-estradiol (0.05, 0.5, or 5.0 mg/pellet, estimated serum levels of 20-25 pg/ml, 100-600 pg/ml, and 1-2 ng/ml, respectively). Animals were sacrificed at 3 weeks and MAO-A and -B activity was assessed in homogenates of heart, liver, lung, uterus, kidney, adrenal and small intestine using 5-hydroxytryptamine and phenylethylamine as substrates. Cortex, amygdala and hypothalamus were microdissected from frozen sections of the brain and were also assayed for MAO-A and -B activity. High dose estrogen (5 mg/pellet) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (-30%, +1%), kidney (-22%, -11%), and uterus (-57%, -35%) (p < 0.05). No significant changes in enzyme activity were observed in heart, adrenal, lung and small intestine. In brain, estrogen (5 mg/pellet) decreased MAO-A activity in the hypothalamus (-28%) and amygdala (-21%), with no significant change seen in MAO-B. Our results suggest that estrogen exerts a tissue-specific, differential regulation of MAO-A and -B activity.