Nucleus Of Meynert Research Articles

Involvement of the basal nucleus of Meynert on regional cerebral cortical vasodilation associated with masticatory muscle activity in rats

We examined the neural mechanisms for increases in regional cerebral blood flow (rCBF) in the neocortex associated with mastication, focusing on the cortical vasodilative system derived from the nucleus basalis of Meynert (NBM). In pentobarbital-anesthetized rats, parietal cortical rCBF was recorded simultaneously with electromyogram (EMG) of jaw muscles, local field potentials of frontal cortex, multi-unit activity of NBM neurons, and systemic mean arterial pressure (MAP). When spontaneous rhythmic EMG activity was observed with cortical desynchronization, an increase in NBM activity and a marked rCBF increase independent of MAP changes were observed. A similar rCBF increase was elicited by repetitive electrical stimulation of unilateral cortical masticatory areas. The magnitude of rCBF increase was partially attenuated by administration of the GABAergic agonist muscimol into the NBM. The rCBF increase persisted after immobilization with systemic muscle relaxant (vecuronium). rCBF did not change when jaw muscle activity was induced by electrical stimulation of the pyramidal tract. The results suggest that activation of NBM vasodilator neurons contributes at least in part to the rCBF increase associated with masticatory muscle activity, and that the NBM activation is induced by central commands from the motor cortex, independently of feedback from brainstem central pattern generator or contracting muscles.

Possible Mechanisms of the Complex Effects of Acetylcholine on Theta Activity, Learning, and Memory

Disturbances of learning and memory are related to the impaired expression of rhythmic activity and phase synchronization in the hippocampus, entorhinal cortex, and other cortical areas. Several structures involved in the generation of the theta rhythm contain cholinergic cells and thus, acetylcholine concentration has to affect the parameters of the rhythm and play a substantial role in learning and memory. Here, we analyzed possible mechanisms of the effect of acetylcholine on the parameters of the theta rhythm in the hippocampus. The complex nature of these mechanisms is related to the effects of the cholinergic input from the medial septum to the hippocampus and the input from cholinergic cells of the pedunculopontine and oral pontine nuclei as well as of the Meynert nucleus on theta activity. Furthermore, the thalamic nucleus reu-niens, which also sends projections to the medial septum, hippocampal CA1 field, and entorhinal cortex, also affects theta activity. The supramamillary, posterior and medial mamillary nuclei of the hypothalamus also influence it via their interaction with the hippocampal formation and septum. Some structures involved in the generation of theta activity have long axon GABAergic cells, which exhibit inhibitory or disinhibitory effects on other structures. Acetylcholine, which contributes to increased excitation in the network involved in the generation of the theta rhythm, can lead to an increase in its expression or power, while the rhythm frequency is determined by inhibition and should increase when the inhibition is weakened.

Tau and TDP-43 accumulation of the basal nucleus of Meynert in individuals with cerebral lobar infarcts or hemorrhage

A previous study reported that a massive cerebral infarct in the territory of the middle cerebral artery (MCA) may be associated with development of neurofibrillary tangles (NFTs) in the ipsilateral basal nucleus of Meynert (BNM). We analyzed 19 cases of an MCA territory infarct and 12 with a putaminal hemorrhage (mean age 82.5 years; female/male ratio 8/23; mean time from stroke onset to autopsy 4182 days). In both groups, 74–100% had a significantly higher rate of phosphorylated tau immunoreactive or Gallyas Braak silver stain-positive neurons on the BNM-affected side than on the BNM-unaffected side. These NFTs were immunoreactive for anti-RD3 and anti-RD4 antibodies, and a triple-band pattern was observed by immunoblot analysis with anti-tau antibody. Most NFTs might be formed within the 5–10 years after stroke onset. There were significantly more TAR DNA-binding protein 43 (TDP43) immunoreactive structures on the BNM-affected side than on the BNM-unaffected side. We showed that many NFTs with TDP43-immunoreactive structures were observed in the ipsilateral BNM associated with a massive cerebral infarct in the MCA territory or a putaminal hemorrhage.

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain.

Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II–VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II–VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

Diffusion Tensor Tractography Studies on Injured Anterior Cingulum Recovery Mechanisms: A Mini-Review.

The cingulum, a major structure in the limbic system, contains the medial cholinergic pathway, which originates from the basalis nucleus of Meynert (Ch 4) in the basal forebrain. The cingulum is involved in various cognitive functions, including memory, attention, learning, motivation, emotion, and pain perception. In this mini-review, 10 studies reporting on recovery mechanisms of injured cinguli in patients with brain injury were reviewed. The recovery mechanisms of the injured anterior cinguli reported in those 10 studies are classified as follows: Mechanism 1, recovery via the normal pathway of the cingulum between the injured cingulum and Ch 4; mechanism 2, recovery through the neural tract between the injured cingulum and the brainstem cholinergic nuclei; mechanism 3, recovery via the lateral cholinergic pathway between the injured cingulum and the white matter of the temporo-occipital lobes; mechanism 4, recovery through the neural tract between the contralesional basal forebrain and the ipsilesional basal forebrain via the genu of the corpus callosum; and mechanism 5, recovery through the neural tract between the injured cingulum and Ch 4 via an aberrant pathway. Elucidation of the recovery mechanisms of injured anterior cinguli might be useful for neurorehabilitation of patients with anterior cingulum injuries. Diffusion tensor tractography appears to be useful in the detection of recovery mechanisms of injured anterior cinguli in patients with brain injury. However, studies on cingulum injury recovery mechanisms are still in the early stages because most of the above studies are case reports confined to a few brain pathologies. Therefore, further studies involving large numbers of subjects with various brain pathologies should be encouraged. In addition, studies on the influencing factors and clinical outcomes associated with each recovery mechanism are warranted.

From eyes-closed to eyes-open: Role of cholinergic projections in EC-to-EO alpha reactivity revealed by combining EEG and MRI.

Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes-closed (EC) resting and attenuates during eyes-open (EO) resting. Research shows that the degree of EC-to-EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC-to-EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG-fMRI was recorded from twenty-one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM-visual cortex functional connectivity increase from EC to EO, the larger the EC-to-EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC-to-EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system.

Nerve growth factor released from collagen scaffolds protects axotomized cholinergic neurons of the basal nucleus of Meynert in organotypic brain slices

BackgroundAlzheimeŕs disease is accompanied by cell death of cholinergic neurons, resulting in cognitive impairment and memory loss. Nerve growth factor (NGF) is the most potent protein to support survival of cholinergic neurons. New MethodOrganotypic brain slices of the basal nucleus of Meynert (nBM) are a valuable tool to study cell death of axotomized cholinergic neurons, as well as protective effects of NGF added into the medium. The aim of the present study is to use collagen scaffolds crosslinked with polyethyleneglycole and load with NGF to target delivery of NGF to organotypic nBM brain slices. ResultsCollagen scaffolds (visualized by incorporating AlexaFluor 488 antibodies) slowly degraded when applied onto organotypic brain slices within 2 weeks in culture. GFAP reactive astrocytes and Iba1+ microglia became visible around the collagen scaffolds 7days after incubation, showing reactive gliosis. Cholinergic neurons of the nBM survived (201±21, n=8) when incubated with 100ng/ml NGF in the medium compared to NGF-free medium (69±12, n=7). Collagen scaffolds loaded with NGF (1ng/2μl scaffold) significantly rescued cholinergic cell death in the nBM brain slices (175±12, n=10), which was counteracted by an anti-NGF antibody (77±5, n=5). Comparison with existing MethodsThe combination of coronal brain slices with biomaterial is a novel and potent tool to selectively study neuroprotective effects. ConclusionsCollagen scaffolds loaded with low amounts of a protein/drug of interest can be easily applied directly onto organotypic brain slices, allowing slow targeted release of a protective molecule. Such an approach is highly useful to optimize CollScaff for further in vivo applications.

ALTERED FUNCTIONAL CONNECTIVITY OF THE BASAL NUCLEUS OF MEYNERT IN MILD COGNITIVE IMPAIRMENT: A RESTING-STATE FMRI STUDY

Cholinergic dysfunction plays an important role in mild cognitive impairment (MCI). The basal nucleus of Meynert (BNM) provides the main source of cortical cholinergic innervation. Previous studies have characterized structural changes of the cholinergic basal forebrain in individuals at risk of developing Alzheimer's disease. However, whether and how functional connectivity of the BNM (BNM-FC) is altered in MCI remains unknown. One-hundred-and-eleven MCI patients and one hundred and seven HCs underwent resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were processed with Statistical Parametric Mapping. BNM-FC was examined via correlation in low frequency fMRI signal fluctuations between the BNM and all other brain voxels. Group difference was tested by covariance analysis to control for age, gender, and years of education. Pearson regression was conducted to evaluate the relationship between the BNM-FC and clinical assessments. Compared with HCs, MCI group showed decreased BNM-FC in the right anterior cingulate cortex (ACC), right putamen, as well as left insula and dorsal striatum, including claustrum, putamen/pallidum and caudate. Further, greater decreases in BNM-FC to these regions were associated with more severe impairment in immediate and delayed recall in MCI patients.

Altered Functional Connectivity of the Basal Nucleus of Meynert in Mild Cognitive Impairment: A Resting-State fMRI Study.

Background: Cholinergic dysfunction plays an important role in mild cognitive impairment (MCI). The basal nucleus of Meynert (BNM) provides the main source of cortical cholinergic innervation. Previous studies have characterized structural changes of the cholinergic basal forebrain in individuals at risk of developing Alzheimer’s disease (AD). However, whether and how functional connectivity of the BNM (BNM-FC) is altered in MCI remains unknown.Objective: The aim of this study was to identify alterations in BNM-FC in individuals with MCI as compared to healthy controls (HCs), and to examine the relationship between these alterations with neuropsychological measures in individuals with MCI.Method: One-hundred-and-one MCI patients and 103 HCs underwent resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were processed with SPM8 and CONN software. BNM-FC was examined via correlation in low frequency fMRI signal fluctuations between the BNM and all other brain voxels. Group differences were examined with a covariance analysis with age, gender, education level, mean framewise displacement (FD) and global correlation (GCOR) as nuisance covariates. Pearson’s correlation was conducted to evaluate the relationship between the BNM-FC and clinical assessments.Result: Compared with HCs, individuals with MCI showed significantly decreased BNM-FC in the left insula extending into claustrum (insula/claustrum). Furthermore, greater decrease in BNM-FC with insula/claustrum was associated with more severe impairment in immediate recall during Auditory Verbal Learning Test (AVLT) in MCI patients.Conclusion: MCI is associated with changes in BNM-FC to the insula/claustrum in relation to cognitive impairments. These new findings may advance research of the cholinergic bases of cognitive dysfunction during healthy aging and in individuals at risk of developing AD.

Proceso de senescencia de los centros mnésicos: Estudio en el hombre y en la rata

The age-related neuronal changes in mnemonic centres were studied in 37 human and 36 rats (Wistar) brains. The age of the brains (without cerebral alterations) was uniformly distributed along the lifspan (16-86 years in humans and 1-36 months in rats). 
 
 The results showed parallel changes in humans and rats. The neuronal loss oscillated between 3 and 64%, mean 32%. Neuronal death was a continuous process, although there were differences according the centres, far instance, the higher loss was found in the first half of lite in the cortex entorhinalis and hippocampus (rat), and the contrary happened in the dorsolateral and basomedial nucleus of amygdala. In other centres, e.gr., mammillar body, basal nucleus of Meynert etc. the loss was quite uniform. 
 
 The modification in nuclear size showed 3 different phases: there was an initial period in which the nuclear area decreased, a second period with an increase and, in the last period, there was a stabilization in humans and a conspicuous decrease in rats. The nuclear enlargement is interpretated as result of the loss of redundance in nervous centres and the stabilization or atrophy as a consequence of loss of the neuronal plasticity.

Morphofunctional Correlation of Excitatory and Depressor Synaptic Processes in Hippocampus, Amygdala and Basal Meynert Nucleus Neurons in Dynamics of Development of Alzheimer's Disease Model Induced by Aβ25-35

Objective: Compensatory mechanisms are responsible for the clinical signs of suppression of neurodegeneration. Intervention into their mechanisms on an example of the ratio of excitatory and depressor synaptic responses will contribute to the development of therapeutic strategies.Methods: After 12-28 weeks (w) of experiment on the model of Alzheimer’s disease (AD), an activity of single neurons of hippocampus (H), Amygdala (Am) and, nucleus basalis of Meynert (NBM) to high frequency stimulation (HFS) of entorhinal cortex (EC) was recorded. The high frequency stimulation of H resulted in an activity of single neurons of the Am and NBM. By means of on-line selection and special mathematical analysis, tetanic potentiation (TP) and depression (TD) with further combination into posttetanic uni and multidirectional sequences, were revealed. In morpho- and histochemical study, the method of revelation of Сa2+- dependent phosphorylation was used.Results: After 12 weeks of experiment on the model of AD, a heavy TD of NBM and Аm neurons to HFS of H, as well as a weak (TD) in H and NBM neurons to HFS of EC were found. TP occurred by the activation of ЕС in the H (TP PTP) and in Am (TP PTD) neurons, equal to and above the norm in neurons of Am to HFS of H. In the neurons of NBM to HFS of EC, the weakest excitation to HFS of H was detected. In the neurons H to HFS of EC, Am and NBM to HFS of H, after 13-28 weeks, TD and tetanic excitation in all cases were low, which indicating on depletion of compensatory opportunities. Morpho- and histo-chemical changes of H, Am and NBM neurons on the model of AD were characterized by total tendency to structural-metabolic dysfunctions, with distortion of forms, central chromatolysis, presence of light ectopic nucleus with increased nucleolus, change reaction of neurofibrills, lack of reaction processes, accumulation of hyper phosphorylated entities and, presence of spaces with the lack of cellular reaction.Conclusion: The absence of expressed depression, presupposed by us as a protector in the present study, makes it necessary to involve pharmacological interventions with a view to its strengthening, and therefore is the subject of the next reports. Electrophysiological data have been confirmed morphologically.

Serum antibodies targeting neurons of the monoaminergic systems in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an autoimmune disease with progressive flaccid paralysis of the extremities. Several auto-antibodies have been identified, binding to myelin, gangliosides, astrocytes or proteins at the nodes of Ranvier. Some epitopes are not confined to the peripheral nerve, suggesting that auto-antibodies may also contribute to symptoms of the central nervous system, which are common in GBS and include anxiety, depression, hallucinations, oneiroid psychosis or fatigue. This notion is supported by treating patients with plasma exchange, resulting in improvement of both central and peripheral symptoms.We analyzed binding of GBS sera to neurons of cholinergic, serotonergic, dopaminergic, nor‐adrenergic or histaminergic nuclei using immunohistochemistry of the rat brain. We hypothesized that GBS sera harbor antibodies against monoaminergic structures in the brain, as these circuits influence larger neuronal networks with relevance for multiple neuropsychiatric symptoms. Indeed, several GBS sera strongly and specifically reacted with monoaminergic neurons, in particular cholinergic nuclei of the diagonal band, neurons of the basal nucleus of Meynert, nor‐adrenergic neurons of the nucleus coeruleus, neurons in the raphe or the ambiguous nucleus. The frequency significantly exceeded those of sera from patients with multiple sclerosis, non-autoimmune neurological disorders and healthy controls.The binding to neuronal surfaces makes it conceivable that the auto-antibodies can interfere with ion channels and receptors and thus contribute to the variable clinical spectrum of neuropsychiatric and autonomic abnormalities in GBS. Future research should include the target identification of promising GBS sera and aim to determine the functional effects of these antibodies.

Resting-State Functional Connectivity of the Basal Nucleus of Meynert in Cigarette Smokers: Dependence Level and Gender Differences.

Numerous studies have characterized impaired cerebral functioning in nicotine-addicted individuals. Whereas nicotine interacts with multiple neurotransmitters in cortical and subcortical circuits, it directly targets the cholinergic system, sourced primarily from the basal nucleus of Meynert (BNM). However, no studies have examined how this cholinergic system is influenced by cigarette smoking. Here, we addressed this gap of research. Using a dataset from the Functional Connectome Projects, we investigated this issue by contrasting seed-based BNM connectivity of 40 current smokers and 170 age- and gender-matched nonsmokers. We followed our data analytic routines in recent work and examined differences between smokers and nonsmokers in men and women combined as well as separately. Compared to nonsmokers, female but not male smokers demonstrated greater positive BNM connectivity to the supplementary motor area, bilateral anterior insula, and right superior temporal/supramarginal gyri as well as greater negative connectivity to the posterior cingulate cortex and precuneus. Further, BNM connectivity to the supplementary motor area is negatively correlated to the Fagerström Test for Nicotine Dependence score in male but not female smokers. Along with a previous report of upregulated nicotinic acetylcholine receptor in male but not female smokers, these new findings highlight functional changes of the cholinergic systems in cigarette smokers. The results suggest sex-specific differences in cholinergic dysregulation and a need for multiple imaging modalities to capture the neural markers of nicotine addiction. Nicotine influences cognition via cholinergic projections of the basal forebrain to the cerebral cortex. This study examined changes in resting-state whole-brain functional connectivity of the BNM in cigarette smokers. The new findings elucidate for the first time sex differences in BNM-cerebral connectivity in cigarette smoking.

The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults.

Background: Methylphenidate (MPH) influences catecholaminergic signaling. Extant work examined the effects of MPH on the neural circuits of attention and cognitive control, but few studies have investigated the effect of MPH on the brain's resting-state functional connectivity (rsFC).Methods: In this observational study, we compared rsFC of a group of 24 healthy adults who were administered an oral 45 mg dose of MPH with a group of 24 age and gender matched controls who did not receive MPH. We focused on three seed regions: basal nucleus of Meynert (BNM), locus coeruleus (LC), and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc), each providing cholinergic, noradrenergic and dopaminergic inputs to the cerebral cortex. Images were pre-processed and analyzed as in our recent work (Li et al., 2014; Zhang et al., 2015). We used one-sample t-test to characterize group-specific rsFC of each seed region and two-sample t-test to compare rsFC between groups.Results: MPH reversed negative connectivity between BNM and precentral gyri. MPH reduced positive connectivity between LC and cerebellum, and induced positive connectivity between LC and right hippocampus. MPH decreased positive VTA/SNc connectivity to the cerebellum and putamen, and reduced negative connectivity to left middle occipital gyrus.Conclusion: MPH had distinct effects on the rsFC of BNM, LC, and VTA/SNc in healthy adults. These new findings may further our understanding of the role of catecholaminergic signaling in Attention Deficit Hyperactivity Disorder (ADHD) and Parkinson's disease and provide insights into the therapeutic mechanisms of MPH in the treatment of clinical conditions that implicate catecholaminergic dysfunction.

Stress alters asenapine-induced Fos expression in the Meynert’s nucleus: response of adjacent hypocretin and melanin-concentrating hormone neurons in rat

Objective: Asenapine (ASE), an atypical antipsychotic drug used in the treatment of schizophrenia, induces Fos expression in forebrain. Effect of ASE on activity of basal nucleus of Meynert (NBM) cells, a part of the striatal–cortical circuits, was studied. We were also interested to reveal whether a chronic unpredictable variable mild stress (CMS) preconditioning might affect the ASE impact.Methods: Rats were divided into as follows: controls-vehicle, controls-ASE, stressed-vehicle and stressed-ASE groups. CMS included restrain, social isolation, crowding, swimming and cold applied for 21 days. On the 22nd day, rats were subcutaneously injected with ASE (0.3 mg/kg) or vehicle (saline 300 μl/rat), 90 min prior euthanizing. After transcardial fixation, brains were cut into 30 μm thick coronal sections. Fos protein presence, as indicator of cell activity, was detected by ABC immunohistochemistry. Hypocretin (Hcrt) and melanin-concentrating hormone (MCH) containing cells were visualized with fluorescent dyes.Results: ASE induced significant increase in Fos expression in NBM in both controls and CMS preconditioned rats in comparison with the related vehicle-treated controls. CMS preconditioning, however, significantly lowered the Fos response to ASE in NBM. From Hrct and MCH cells, only Hcrt ones displayed Fos presence in response to ASE.Discussion: This study demonstrates for the first time that ASE may target a special group of cells occupying NBM, which effect can be modulated by CMS preconditioning. This finding extends a view that ASE impact may extend beyond the classical forebrain target areas common for the action of all antipsychotics and might be helpful in the identification of sites and side effects of its therapeutic actions.

An open-label pilot study with high-dose thiamine in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by motor symptoms (bradykinesia, tremor, rigidity, postural instability) and non-motor symptoms (hyposmia, sleep disorders, autonomic and sphincteric dysfunctions, fatigue, pain, depression, and cognitive disorders) (Sprenger and Poewe, 2013). The neuropathological hallmark of PD is the degeneration of the pigmented dopaminergic neurons in the substantia nigra; other nuclei involved in neurodegeneration are locus coeruleus, reticular nuclei of brain stem, dorsal motor nucleus of vagus, basal nucleus of Meynert, amygdala, CA2 area of hippocampus, and frontal cortex. At the onset of parkinsonian symptoms, the neuronal loss is quite 70% in the lateral ventral part and 50% in the caudal part of the substantia nigra (Kordower et al., 2013). For this reason, and for the long time between the cellular onset and the clinical onset of the disease, it is mandatory to develop new therapies with disease-modifying and neuroprotective actions. The gold standard therapy for PD is always levodopa, while other currently validated treatments are dopamine agonists, cathecol-O-methyltransferase inhibitors, monoamine-oxidase-B inhibitors, and amantadine (Poewe et al., 2010; Sprenger and Poewe, 2013).

Intraneuronal amyloid-β accumulation in basal forebrain cholinergic neurons: a marker of vulnerability, yet inversely related to neurodegeneration

Intraneuronal amyloid-β accumulation in basal forebrain cholinergic neurons: a marker of vulnerability, yet inversely related to neurodegeneration

Recovery of injured cingulum in a patient with traumatic brain injury.

Recovery of injured cingulum in a patient with traumatic brain injury.

REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer 's disease

AimsThe cholinergic system is one of the neurotransmitter systems altered in Alzheimer's disease (AD), the most common form of human dementia. The objective of this work was to determine the REST/NRSF involvement in altered ChAT expression in the neocortex and hippocampus of an AD transgenic mouse (homozygous 3xTg-AD) that over-expresses 3 proteins, amyloid-β precursor protein, presenilin-1, and tau, all of which are associated with AD and cause cellular degeneration. Main methodsTwo groups (WT and 3xTg-AD) of 11-month-old female mice were analyzed and compared. Half of the brains of each group were used for ChAT immunohistochemistry, and Western Blot analyses of ChAT and REST/NRSF were performed on the other half. Key findingsWe observed significant decreases in the number of ChAT-immunoreactive cells in the Meynert nucleus and of fibers in the frontal motor cortex and hippocampal CA1 area in transgenic mice compared with control mice. An increased level of REST/NRSF protein and a reduction of ChAT protein expression in the 3xTg-AD mice compared with their controls were also found in both in the latter two cerebral regions. SignificanceThe increased REST/NRSF expression reported here and its effect on the regulatory region for ChAT transcription could explain the decreased expression of ChAT in the 3xTg-AD mouse; these findings may be associated with the degeneration observed in AD.

Resting state functional connectivity of the basal nucleus of Meynert in humans: In comparison to the ventral striatum and the effects of age

The basal nucleus of Meynert (BNM) provides the primary cholinergic inputs to the cerebral cortex. Loss of neurons in the BNM is linked to cognitive deficits in Alzheimer's disease and other degenerative conditions. Numerous animal studies described cholinergic and non-cholinergic neuronal responses in the BNM; however, work in humans has been hampered by the difficulty of defining the BNM anatomically. Here, on the basis of a previous study that delineated the BNM of post-mortem human brains in a standard stereotaxic space, we sought to examine functional connectivity of the BNM, as compared to the nucleus accumbens (or ventral striatum, VS), in a large resting state functional magnetic resonance imaging data set. The BNM and VS shared but also showed a distinct pattern of cortical and subcortical connectivity. Compared to the VS, the BNM showed stronger positive connectivity with the putamen, pallidum, thalamus, amygdala and midbrain, as well as the anterior cingulate cortex, supplementary motor area and pre-supplementary motor area, a network of brain regions that respond to salient stimuli and orchestrate motor behavior. In contrast, compared to the BNM, the VS showed stronger positive connectivity with the ventral caudate and medial orbitofrontal cortex, areas implicated in reward processing and motivated behavior. Furthermore, the BNM and VS each showed extensive negative connectivity with visual and lateral prefrontal cortices. Together, the distinct cerebral functional connectivities support the role of the BNM in arousal, saliency responses and cognitive motor control and the VS in reward related behavior. Considering the importance of BNM in age-related cognitive decline, we explored the effects of age on BNM and VS connectivities. BNM connectivity to the visual and somatomotor cortices decreases while connectivity to subcortical structures including the midbrain, thalamus, and pallidum increases with age. These findings of age-related changes of cerebral functional connectivity of the BNM may facilitate research of the neural bases of cognitive decline in health and illness.