Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.
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Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice. (+info)
Cholinergic modulation of experience-dependent plasticity in human auditory cortex.
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The factors that influence experience-dependent plasticity in the human brain are unknown. We used event-related functional magnetic resonance imaging (fMRI) and a pharmacological manipulation to measure cholinergic modulation of experience-dependent plasticity in human auditory cortex. In a differential aversive conditioning paradigm, subjects were presented with high (1600 Hz) and low tones (400 Hz), one of which was conditioned by pairing with an electrical shock. Prior to presentation, subjects were given either a placebo or an anticholinergic drug (0.4 mg iv scopolamine). Experience-dependent plasticity, expressed as a conditioning-specific enhanced BOLD response, was evident in auditory cortex in the placebo group, but not with scopolamine. This study provides in vivo evidence that experience-dependent plasticity, evident in hemodynamic changes in human auditory cortex, is modulated by acetylcholine. (+info)
Signals invisible to the collicular and magnocellular pathways can capture visual attention.
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The retinal projection to the superior colliculus is thought to be important both for stimulus-driven eye movements and for the involuntary capture of attention. It has further been argued that eye-movement planning and attentional orienting share common neural mechanisms. Electrophysiological studies have shown that the superior colliculus receives no direct projections from short-wave-sensitive cones (S cones), and, consistent with this, we found that irrelevant peripheral stimuli visible only to S cones did not produce the saccadic distractor effect produced by luminance stimuli. However, when involuntary orienting was tested in a Posner cueing task, the same S-cone stimuli had normal attentional effects, in that they accelerated or delayed responses to subsequent targets. We conclude that involuntary attentional shifts do not require signals in the direct collicular pathway, or indeed the magnocellular pathway, as our S-cone stimuli were invisible to this channel also. (+info)
A new area in the human brain associated with learning and memory: immunohistochemical and functional MRI analysis.
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Previous studies identified a new brain area, the marginal division (MrD), at the caudomedial border of the neostriatum in the brain of the rat, cat and monkey. The MrD was distinguishable from the rest of the striatum by the presence of spindle-shaped neurons, specific connections, and dense immunoreactivity for neuropeptides and monoamines in fibers, terminals and neuronal somata. Behavioral testing demonstrated that the MrD contributes to learning and memory in the rat. In the present study, the structure and the function of the MrD were investigated in the human brain. The presence of spindle-shaped neurons and the distribution of neurotransmitters in the MrD were evaluated by immunocytochemical methods. The function of the MrD was identified with functional magnetic resonance imaging (fMRI) of healthy volunteers tested with an auditory digital working memory task. Highly active areas were observed in the prefrontal cortex and MrD with left sided predominance during performance of the task, but other parts of the neostriatum were not excited and the MrD was not activated in a control test of non-working memory. The results of the present investigation therefore indicate the existence of a new area associated with learning and memory function in the human brain. The MrD probably plays an important role in the execution of digital working memory and appears to link the limbic system and the basal nucleus of Meynert. The MrD may also be involved in the mechanism of Alzheimer's disease. (+info)
Raphe magnus neurons respond to noxious colorectal distension.
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Physiological studies of neurons in raphe magnus (RM) and the adjacent nucleus reticularis magnocellularis (NRMC) have demonstrated that the response to noxious cutaneous stimulation predicts the response to opioid administration and therefore a cell's functional role in nociceptive modulation. Although visceral stimulation, like opioids, elicits antinociception, little is known about how RM and NRMC cells respond to visceral stimulation. Therefore RM and NRMC cells were tested for their responses to both colorectal distension (CRD) and noxious cutaneous heat in halothane-anesthetized rats. Less than a third of serotonergic cells responded to CRD with small increases or decreases in discharge rate. In contrast, almost two-thirds of nonserotonergic cells responded to CRD stimulation with either excitatory (35%) or inhibitory (30%) responses to CRD. The response to heat did not predict the response to CRD with nearly equal proportions of heat-excited, -inhibited, and -unaffected cells being excited, inhibited, or unaffected by CRD. The dissociation between the responses to cutaneous heat and CRD demonstrates that cell classes based on the response to noxious heat are not homogeneous and may play multiple functional roles. (+info)
Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease.
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Cell cycle events play a major role in the loss of neurons in advanced Alzheimer's disease (AD). It is currently unknown, however, whether the same is true for the neuronal losses in early disease stages. To explore this issue we analyzed brain autopsy material from individuals clinically categorized with mild cognitive impairment (MCI), many if not most of whom will progress to AD. Immunocytochemistry for three cell cycle-related proteins, proliferating cell nuclear antigen, cyclin D, and cyclin B, was performed on sections from hippocampus, basal nucleus of Meynert, and entorhinal cortex. The results obtained from MCI cases were compared with material from individuals diagnosed with AD and those without cognitive impairment. In both hippocampus and basal nucleus, there was a significant percentage of cell cycle immunopositive neurons in the MCI cases. These percentages were similar to those found in the AD cases but significantly higher than non-cognitively impaired controls. In entorhinal cortex, the density of cell cycle-positive neurons was greater in MCI than in AD. However, we observed large variations in the percentages of immunopositive neurons from individual to individual. These findings lend support to the hypothesis that both the mechanism of cell loss (a cell cycle-induced death) and the rate of cell loss (a slow atrophy over several months) are identical at all stages of the AD disease process. The implication of the findings for human clinical trials is discussed. (+info)
A1 receptor and adenosinergic homeostatic regulation of sleep-wakefulness: effects of antisense to the A1 receptor in the cholinergic basal forebrain.
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We hypothesized that adenosine, acting via the A1 receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of wakefulness-promoting neurons in the basal forebrain. Adenosine A1 receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A1 receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. After microdialysis perfusion of A1 receptor antisense in the basal forebrain, spontaneous levels of sleep-wakefulness showed a significant reduction in non-rapid eye movement (REM) sleep with an increase in wakefulness. After 6 hr of sleep deprivation, the antisense-treated animals spent a significantly reduced amount of time in non-REM sleep, with postdeprivation recovery sleep hours 2-5 showing a reduction of approximately 50-60%. There was an even greater postdeprivation reduction in delta power (60-75%) and a concomitant increase in wakefulness. All behavioral state changes returned to control (baseline) values after the cessation of antisense administration. Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A1 receptor suppressed A1 receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A1 receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep. (+info)
Nitric oxide-mediated cortical activation: a diffuse wake-up system.
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Nitric oxide (NO) has been implicated in some of the central pathways engaged in the regulation of the sleep-wake cycle. The existence of nitric oxide synthase (NOS) in the cholinergic basal forebrain (BF) cells projecting to the cortex suggests a role for NO in the activation induced by the BF during arousal. We tested, in the anesthetized cat, the hypothesis that inhibition of NOS would decrease the ability of BF cholinergic fibers to induce cortical activation. In control conditions, BF stimulation evoked an awake-like EEG pattern (i.e., a decrease in the low-frequency-high-amplitude oscillatory activity and an increase in the high-frequency-low-amplitude activity). After blocking NOS activity, the capacity of BF stimulation to induce cortical activation was strongly impaired. Furthermore, voltammetric measurements of NO levels revealed an increase in cortical NO after BF stimulation, also blocked by systemic NOS inhibition. These results indicate that the blockade of NOS activity significantly reduces the ability of BF stimulation to induce changes in the EEG pattern and suggest a role for NO in the BF-cholinergic system implicated in arousal mechanisms. (+info)