-
Neuroscience Jan 2017The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs)....
The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12-17months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.
Topics: Animals; Attention; Basal Forebrain; Cell Count; Cell Size; Choline; Cholinergic Neurons; Dietary Supplements; Disease Models, Animal; Down Syndrome; Female; Male; Maternal Nutritional Physiological Phenomena; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mothers; Organ Size; Pregnancy; Random Allocation
PubMed: 27840230
DOI: 10.1016/j.neuroscience.2016.11.001 -
International Journal of Molecular... Jan 2021Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the... (Review)
Review
Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer's disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer's disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer's disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer's disease and potential therapeutic implications.
Topics: Acetylcholine; Adrenergic Neurons; Alzheimer Disease; Animals; Basal Nucleus of Meynert; Cholinergic Neurons; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Locus Coeruleus; Memory; Norepinephrine; Receptors, Muscarinic; Receptors, Nicotinic; Signal Transduction
PubMed: 33525357
DOI: 10.3390/ijms22031273 -
Journal of Chemical Neuroanatomy Sep 2011The transcription factor Forkhead box protein 2 (FoxP2) is expressed in two cell groups of the brainstem that have been implicated in sodium appetite regulation: the... (Review)
Review
The transcription factor Forkhead box protein 2 (FoxP2) is expressed in two cell groups of the brainstem that have been implicated in sodium appetite regulation: the pre-locus coeruleus (pre-LC) and parabrachial nucleus--external lateral-inner subdivision (PBel-inner). Because the connections of these two groups are unknown, neuroanatomical tracing methods were used to define their central projections. The pre-LC outputs were first analyzed using an anterograde axonal tracer--Phaseolus vulgaris leucoagglutinin (PHAL) to construct a brain map. Next, we examined whether the FoxP2 immunoreactive (FoxP2+) neurons of the pre-LC contribute to these projections using a retrograde neuronal tracer--cholera toxin β-subunit (CTb). CTb was injected into selected brain regions identified in the anterograde tracing study. One week later the rats were killed, and brainstem sections were processed by a double immunohistochemical procedure to determine whether the FoxP2+ neurons in the pre-LC and/or PBel-inner contained CTb. FoxP2+ pre-LC neurons project to: (1) ventral pallidum; (2) substantia innominata and bed nucleus of the stria terminalis; (3) paraventricular, central medial, parafascicular, and subparafascicular parvicellular thalamic nuclei; (4) paraventricular (PVH), lateral, perifornical, dorsomedial (DMH), and parasubthalamic hypothalamic nuclei; and (5) ventral tegmental area (VTA), periaqueductal gray matter (PAG), dorsal and central linear raphe nuclei. FoxP2+ PBel-inner neurons project to the PVH and DMH, with weaker connections to the LHA, VTA, and PAG. Both the pre-LC and PBel-inner project to central sites implicated in sodium appetite, and related issues, including foraging behavior, hedonic responses to salt intake, sodium balance, and cardiovascular regulation, are discussed.
Topics: Animals; Appetite Regulation; Brain Stem; Forkhead Transcription Factors; Neural Pathways; Neurons; Rats; Sodium, Dietary
PubMed: 21605659
DOI: 10.1016/j.jchemneu.2011.05.003 -
The Journal of Comparative Neurology May 2017The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic...
The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic sleepiness and cataplexy. The orexin neurons excite wake-promoting neurons in the basal forebrain (BF), and a reciprocal projection from the BF back to the orexin neurons may help promote arousal and motivation. The BF contains at least three different cell types (cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic neurons) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Given the neurochemical and anatomical heterogeneity of the BF, we mapped the pattern of BF projections to the orexin neurons across multiple BF regions and neuronal types. We performed conditional anterograde tracing using mice that express Cre recombinase only in neurons producing acetylcholine, glutamate, or GABA. We found that the orexin neurons are heavily apposed by axon terminals of glutamatergic and GABAergic neurons of the substantia innominata (SI) and magnocellular preoptic area, but there was no innervation by the cholinergic neurons. Channelrhodopsin-assisted circuit mapping (CRACM) demonstrated that glutamatergic SI neurons frequently form functional synapses with the orexin neurons, but, surprisingly, functional synapses from SI GABAergic neurons were rare. Considering their strong reciprocal connections, BF and orexin neurons likely work in concert to promote arousal, motivation, and other behaviors. J. Comp. Neurol. 525:1668-1684, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Basal Forebrain; Female; Image Processing, Computer-Assisted; Immunohistochemistry; Mice; Microscopy, Confocal; Neural Pathways; Neurons; Orexins
PubMed: 27997037
DOI: 10.1002/cne.24158 -
Dementia & Neuropsychologia 2013Meynert described the "loop of the peduncular foot" and its ganglion and related them to Reil's and Gratiolet's from which he apparently built up his findings....
Meynert described the "loop of the peduncular foot" and its ganglion and related them to Reil's and Gratiolet's from which he apparently built up his findings. Koelliker renamed the ganglion with the eponymous designation (Meynert's basal ganglion), a name which endures to the present day, and described its topographical spread in relation to neighboring structures. Meynert and Koelliker also described aspects of cell composition of the ganglion (or nucleus) with a better account of the latter. Both, together with Reil and Gratiolet, were the outstanding personalities of the 19 century who performed the pioneering studies on basal formations of the forebrain. After these works, a considerable body of research appeared in the 20 century, with a focus on Meynert's basal nucleus and related structures. The development of further knowledge about these structures revealed their great importance in the activity of the brain, as evidenced in both normal and pathological states.
PubMed: 29213870
DOI: 10.1590/S1980-57642013DN74000013 -
Translational Psychiatry Sep 2022Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The...
Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p > 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.
Topics: Basal Forebrain; Basal Nucleus of Meynert; Cholinergic Agents; Humans; Psychotic Disorders; Transcriptome
PubMed: 36050318
DOI: 10.1038/s41398-022-02136-0 -
Frontiers in Aging Neuroscience 2022Dementia with Lewy bodies (DLB) is a type of dementia often diagnosed in older patients. Since its initial symptoms range from delirium to psychiatric and cognitive...
BACKGROUND
Dementia with Lewy bodies (DLB) is a type of dementia often diagnosed in older patients. Since its initial symptoms range from delirium to psychiatric and cognitive symptoms, the diagnosis is often delayed.
OBJECTIVES
In our study, we evaluated the magnetic resonance imaging (MRI) of patients suffering from DLB in correlation with their initial symptoms taking a new pragmatic approach entailing manual measurements in addition to an automated volumetric analysis of MRI.
METHODS
A total of 63 patients with diagnosed DLB and valid 3D data sets were retrospectively and blinded evaluated. We assessed atrophy patterns (1) manually for the substantia innominata and (2) FastSurfer for the most common supratentorial regions. Initial symptoms were categorized by (1) mild cognitive impairment (MCI), (2) psychiatric episodes, and (3) delirium.
RESULTS
Manual metric MRI measurements revealed moderate, but significant substantia-innominata (SI) atrophy in patients with a psychiatric onset. FastSurfer analysis revealed no regional volumetric differences between groups.
CONCLUSION
The SI in patients with DLB and a psychiatric-onset is more atrophied than that in patients with initial MCI. Our results suggest potential differences in SI between DLB subtypes at the prodromal stage, which are useful when taking a differential-diagnostic approach. This finding should be confirmed in larger patient cohorts.
PubMed: 36274999
DOI: 10.3389/fnagi.2022.815813 -
Brain : a Journal of Neurology Aug 2022Cognitive deficits in Alzheimer's disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The...
Cognitive deficits in Alzheimer's disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-β and phosphorylated-tau pathology at autopsy. To understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimer's disease, we used a combined post-mortem in situ MRI and histopathology approach. A total of 19 Alzheimer's disease (10 amnestic and nine non-amnestic) and nine non-neurological control donors underwent 3 T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed for amyloid-β, phosphorylated-tau and choline acetyltransferase. Compared to controls, we observed an MRI-derived volume reduction and altered microstructural integrity of the nucleus basalis of Meynert in Alzheimer's disease donors. Furthermore, decreased cholinergic cell density was associated with reduced integrity of the nucleus and its tracts to the temporal lobe, specifically to the temporal pole of the superior temporal gyrus, and the parahippocampal gyrus. Exploratory post hoc subgroup analyses indicated that cholinergic cell density could be associated with cortical tract alterations in amnestic Alzheimer's disease donors only. Our study illustrates that in Alzheimer's disease, cholinergic degeneration in the nucleus basalis of Meynert may contribute to damaged cortical projections, specifically to the temporal lobe, leading to cognitive deterioration.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Basal Forebrain; Basal Nucleus of Meynert; Cell Count; Cholinergic Agents; Humans
PubMed: 35259207
DOI: 10.1093/brain/awac093 -
Scientific Reports Jul 2020Dissection of the neural circuits of the cerebral cortex is essential for studying mechanisms underlying brain function. Herein, combining a retrograde rabies tracing...
Dissection of the neural circuits of the cerebral cortex is essential for studying mechanisms underlying brain function. Herein, combining a retrograde rabies tracing system with fluorescent micro-optical sectional tomography, we investigated long-range input neurons of corticotropin-releasing hormone containing neurons in the six main cortical areas, including the prefrontal, somatosensory, motor, auditory, and visual cortices. The whole brain distribution of input neurons showed similar patterns to input neurons distributed mainly in the adjacent cortical areas, thalamus, and basal forebrain. Reconstruction of continuous three-dimensional datasets showed the anterior and middle thalamus projected mainly to the rostral cortex whereas the posterior and lateral projected to the caudal cortex. In the basal forebrain, immunohistochemical staining showed these cortical areas received afferent information from cholinergic neurons in the substantia innominata and lateral globus pallidus, whereas cholinergic neurons in the diagonal band nucleus projected strongly to the prefrontal and visual cortex. Additionally, dense neurons in the zona incerta and ventral hippocampus were found to project to the prefrontal cortex. These results showed general patterns of cortical input circuits and unique connection patterns of each individual area, allowing for valuable comparisons among the organisation of different cortical areas and new insight into cortical functions.
Topics: Animals; Brain; Brain Mapping; Corticotropin-Releasing Hormone; Genetic Vectors; Globus Pallidus; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Neurons; Thalamus
PubMed: 32699360
DOI: 10.1038/s41598-020-68115-x -
Neurobiology of Disease Feb 2023Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions....
Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM.
Topics: Humans; Alzheimer Disease; Basal Forebrain; Basal Nucleus of Meynert; Cognitive Dysfunction; Amyloid beta-Peptides
PubMed: 36586468
DOI: 10.1016/j.nbd.2022.105983