Degeneration of rat cholinergic basal forebrain neurons and reactive changes in nerve growth factor expression after chronic neurotoxic injury—I. Degeneration and plastic response of basal forebrain neurons

doi:10.1016/0306-4522(94)00526-B

Neuroscience

Volume 65, Issue 3, April 1995, Pages 633-645

https://doi.org/10.1016/0306-4522(94)00526-B Get rights and content

Abstract

The process of degeneration and dendritic reorganization of cholinergic neurons was investigated in the rat basal forebrain under the conditions of chronic neurotoxic injury induced by long-term consumption of ethanol. After 28 weeks of ethanol treatment (20% v/v), both the number of cholinergic neurons, such as the activity of choline acetyltransferase and the synthesis and content of acetylcholine, were decreased by about 60–80%. The number of cholinergic neurons showing a positive hybridization signal to choline acetyltransferase messenger RNA was decreased to a similar extent. On the contrary, the reduction in the number of neurons immunoreactive for nerve growth factor receptor p75, which in control brains is highly co-localized with the expression of choline acetyltransferase, was much less pronounced and reached only 20–30%. The loss of choline acetyltransferase expression was associated with a cellular hypertrophy. Neurons which had survived the neurotoxic damage, furthermore, showed a remodelling of the dendritic organization which was quantitatively investigated after Golgi impregnation. This process of dendritic reorganization was mainly characterized by an increase in number and length of terminal dendritic segments.

The results indicate that under the conditions of the present paradigm of chronic neurodegeneration, a certain number of cholinergic neurons persists in a forms where they lost their ability to express detectable amounts of choline acetyltransferase messenger RNA and the enzyme protein. Persisting neurons, however, show both expression of nerve growth factor receptor p75 and signs of perikaryal and dendritic growth. It might, therefore, be hypothesized that chronic degeneration of cholinergic basal forebrain neurons triggers reactive attempts of repair which involve the action of trophic factors such as nerve growth factor.

References (87)

AllenS.J. et al.
Normal β-NGF content in Alzheimer's disease cerebral cortex and hippocampus
Neurosci. Lett.
(1991)
ArendtTh. et al.
Cholinergic system and memory in the rat: effects of chronic ethanol, embryonic basal forebrain brain transplants and excitotoxic lesions of the cholinergic basal forebrain projection system
Neuroscience
(1989)
ArendtTh. et al.
Perisomatic sprouts immunoreactive for nerve growth factor receptor and eeurofibrillary degeneration affect different neuronal populations in the basal nucleus in patients with Alzheimer's disease
Neurosci. Lett.
(1992)
ArendtTh. et al.
Degeneration of rat cholinergic basal forebrain neurons and reactive changes in nerve growth factor expression after chronic neurotoxic injury—II. Reactive expression of the nerve growth factor gene in astrocytes
Neuroscience
(1995)
ArendtTh. et al.
Dendritic changes in the basal nucleus of Meynert and in the diagonal band nucleus in Alzheimer's disease—a quantitative Golgi investigation
Neuroscience
(1986)
AubryJ.M. et al.
Coexpression of dopamine-D2 and substance-P (neurokinin-1) receptor messenger-RNAs by a subpopulation of cholinergic neurons in the rat striatum
Neuroscience
(1993)
BallarinM. et al.
Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain
Expl Neurol.
(1991)
BeracocheaD. et al.
Neuroanatomical effects of chronic ethanol consumption on dorsomedial and anterior thalamic nuclei and on substantia innominata in mice
Neurosci. Lett.
(1987)
Cadete-LeiteA. et al.
Alcohol withdrawal does not impede hippocampal granule cell progressive loss in chronic alcohol-fed rats
Neurosci. Lett.
(1988)
ColemanP.D. et al.
Stability of dendrites in cortical barrels of C57BI/6N mice between 4 and 45 months
Neurobiol. Aging
(1986)

ColemanP.D. et al.

Neuron numbers and dendritic extent in normal aging and Alzheimer's disease

Neurobiol Aging

(1987)

ConnorJ.R. et al.

A Golgi study of the superficial pyramidal cells of the somatosensory cortex of socially reared old adult rats

Expl Neurol.

(1982)

CuppC.J. et al.

Age-related changes in prefrontal cortex ofMacaca mulatta: quantitative analysis of dendritic branching patterns

Expl Neurol.

(1980)

DeLacalleS. et al.

Differential changes in cell-size and number in topographic subdivisions of human basal nucleus in normal aging

Neuroscience

(1991)

Dugich-DjordjevicM.M. et al.

Regionally specific and rapid increases in brain-derived neurotrophic factor messenger RNA in the adult rat brain following seizures induced by systemic administration of kainic acid

Neuroscience

(1992)

DurandD. et al.

Ethanol-induced dendritic alterations in hippocampal granule cells

Brain Res.

(1989)

FloodD.G. et al.

Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia

Brain Res.

(1987)

FloodD.G. et al.

Dendritic extent in human CA_2–3 hippocampal pyramidal neurons in normal aging and senile dementia

Brain Res.

(1987)

FritschyJ.M. et al.

Quantitative changes in morphological parameters in the developing visual cortex of the marmoset monkey

Devl Brain Res.

(1986)

GasserU.E. et al.

Time course of the elevation of nerve growth factor (NGF) content in the hippocampus and septum following lesions of the septohippocampal pathway in rat

Brain Res.

(1986)

GnahnH. et al.

NGF mediated increase in choline acetyltransferase (ChAT) in the neonatal forebrain: evidence for a physiological role of NGF in the brain?

Devl Brain Res.

(1983)

HeftiF. et al.

Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septohippocampal lesions

Brain Res.

(1984)

HellwegR. et al.

Nerve growth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory impairments

Brain Res.

(1990)

HolmesW.R.

The role of dendritic diameters in maximizing the effectiveness of synaptic inputs

Brain Res.

(1989)

HorwitzB.

Neuronal plasticity: how changes in dendritic architecture can effect the spread of postsynaptic potentials

Brain Res.

(1981)

IsacksonP.J. et al.

BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction different from NGF

Neuron

(1991)

IshiiK. et al.

Complementary DNAs for choline acetyltransferase from spinal cords of rat and mouse: nucleotide sequences, expression in mammalian cells, andin situ hybridization

Molec. Brain Res.

(1990)

KingM.A. et al.

Alterations and recovery of dendritic spine density in rat hippocampus following long-term ethanol ingestion

Brain Res.

(1988)

KiyotaY. et al.

Increase in basic fibroblast nerve growth factor-like immunoreactivity in rat brain after forebrain ischemia

Brain Res.

(1991)

KorschingS. et al.

Cholinergic denervation of the rat hippocampus by fimbrial transection leads to a transient accumulation of nerve growth factor (NGF) without change in mRNA content

Neurosci. Lett.

(1986)

LorezH.P. et al.

Effect of bilateral decortication on nerve growth factor content in basal nucleus and neostriatum of adult rat brain

Brain Res.

(1988)

LorezH.P. et al.

Nerve growth factor increases in adult rat brain after hypoxic injury

Neurosci. Lett.

(1989)

Nieto-SampedroM. et al.

Early release of glia maturation factor and acidic fibroblast growth factor after rat brain injury

Neurosci. Lett.

(1988)

OhJ.D. et al.

Cholinergic neurons in the rat central nervous system demonstrated byin situ hybridization of choline acetyltransferase mRNA

Neuroscience

(1992)

RocamoraN. et al.

Limbic seizures induce a differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3, in the rat hippocampus

Molec. Brain Res.

(1992)

RogersJ. et al.

Senescent microstructural changes in rat cerebellum

Brain Res.

(1984)

RoozendaalB. et al.

Changes in vasopressin cells of the rat suprachiasmatic nucleus with aging

Brain Res.

(1987)

StopaE.G. et al.

Basic fibroblast growth factor in Alzheimer's disease

Biochem. biophys. Res. Commun.

(1990)

UchidaY. et al.

Alzheimer's disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats

Biochem. biophys. Res. Commun.

(1988)

UemuraE.

Age-related changes in the subiculum ofMacaca mulatta: dendritic branching pattern

Expl Neurol.

(1985)

WeskampG. et al.

Fimbria-fornix lesion increases nerve growth factor content in adult rat septum and hippocampus

Neurosci. Lett.

(1986)

ArendtTh.

The cholinergic deafferentation of the cerebral cortex induced by chronic consumption of alcohol: reversal by cholinergic drugs and transplantation

ArendtTh. et al.

Cholinergic-rich brain transplants reverse alcohol-induced memory deficits

Nature

(1988)

Cited by (52)

Neonatal ethanol causes profound reduction of cholinergic cell number in the basal forebrain of adult animals
2021, Alcohol
In animal models that mimic human third-trimester fetal development, ethanol causes substantial cellular apoptosis in the brain, but for most brain structures, the extent of permanent neuron loss that persists into adulthood is unknown. We injected ethanol into C57BL/6J mouse pups at postnatal day 7 (P7) to model human late-gestation ethanol toxicity, and then used stereological methods to investigate adult cell numbers in several subcortical neurotransmitter systems that project extensively in the forebrain to regulate arousal states. Ethanol treatment caused especially large reductions (34–42%) in the cholinergic cells of the basal forebrain, including cholinergic cells in the medial septal/vertical diagonal band nuclei (Ch1/Ch2) and in the horizontal diagonal band/substantia innominata/nucleus basalis nuclei (Ch3/Ch4). Cell loss was also present in non-cholinergic basal forebrain cells, as demonstrated by 34% reduction of parvalbumin-immunolabeled GABA cells and 25% reduction of total Nissl-stained neurons in the Ch1/Ch2 region. In contrast, cholinergic cells in the striatum were reduced only 12% by ethanol, and those of the brainstem pedunculopontine/lateral dorsal tegmental nuclei (Ch5/Ch6) were not significantly reduced. Similarly, ethanol did not significantly reduce dopamine cells of the ventral tegmental area/substantia nigra or serotonin cells in the dorsal raphe nucleus. Orexin (hypocretin) cells in the hypothalamus showed a modest reduction (14%). Our findings indicate that the basal forebrain is especially vulnerable to alcohol exposure in the late gestational period. Reduction of cholinergic and GABAergic projection neurons from the basal forebrain that regulate forebrain arousal may contribute to the behavioral and cognitive deficits associated with neonatal ethanol exposure.
Effects of chronic alcohol consumption and withdrawal on the cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei of the rat: An unbiased stereological study
2020, NeuroToxicology
Citation Excerpt :
The finding in the present study that the total number of PPT and LDT cholinergic neurons was also unchanged 2 months after ethanol withdrawal reinforces the view that these neurons are particularly resistant to ethanol exposure, at least when compared with the cholinergic neurons of the medial septum/vertical limb of the diagonal band of Broca, where ethanol withdrawal leads to a further decreased in their total number (Cadete-Leite et al., 2003). The apparent lack of vulnerability of PPT and LDT cholinergic neurons to prolonged ethanol exposure is particularly interesting in view of the fact that under identical experimental conditions there is a decrease in the number of cholinergic neurons in the basal forebrain, namely the medial septum, vertical limb of the diagonal band of Broca, horizontal limb of the diagonal band of Broca and nucleus basalis (Arendt et al., 1988, 1995; Savage et al., 2000; Cadete-Leite et al., 2003). It is possible that the higher resistance of mesopontine cholinergic neurons to chronic alcohol exposure relative to their basal forebrain counterparts might be related to some particular features of these neurons.
The brain cholinergic system comprises two main recognized subdivisions, the basal forebrain and the brainstem cholinergic systems. The effects of chronic alcohol consumption on the basal forebrain cholinergic nuclei have been investigated extensively, but there is only one study that has examined those effects on the brainstem cholinergic nuclei. The last one comprises the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei, which are known to give origin to the main cholinergic projection to the ventral tegmental area, a key brain region of the neural circuit, the mesocorticolimbic system, that mediates several behavioral and physiological processes, including reward. In the present study, we have examined, using stereological methods, the effects of chronic alcohol consumption (6 months) and subsequent withdrawal (2 months) on the total number and size of PPT and LDT choline acetyltransferase (ChAT)-immunoreactive neurons. The total number of PPT and LDT ChAT-immunoreactive neurons was unchanged in ethanol-treated and withdrawn rats. However, ChAT-immunoreactive neurons were significantly hypertrophied in ethanol-treated rats, an alteration that did not revert 2 months after ethanol withdrawal. These results show that prolonged exposure to ethanol leads to long-lasting, and potentially irreversible, cytoarchitectonic and neurochemical alterations in the brainstem cholinergic nuclei. These alterations suggest that the alcohol-induced changes in the brainstem cholinergic nuclei might play a role in the mechanisms underlying the development of addictive behavior to alcohol.
Aging with alcohol-related brain damage: Critical brain circuits associated with cognitive dysfunction
2019, International Review of Neurobiology
Alcoholism is associated with brain damage and impaired cognitive functioning. The relative contributions of different etiological factors, such as alcohol, thiamine deficiency and age vulnerability, to the development of alcohol-related neuropathology and cognitive impairment are still poorly understood. One reason for this quandary is that both alcohol toxicity and thiamine deficiency produce brain damage and cognitive problems that can be modulated by age at exposure, aging following alcohol toxicity or thiamine deficiency, and aging during chronic alcohol exposure. Pre-clinical models of alcohol-related brain damage (ARBD) have elucidated some of the contributions of ethanol toxicity and thiamine deficiency to neuroinflammation, neuronal loss and functional deficits. However, the critical variable of age at the time of exposure or long-term aging with ARBD has been relatively ignored. Acute thiamine deficiency created a massive increase in neuroimmune genes and proteins within the thalamus and significant increases within the hippocampus and frontal cortex. Chronic ethanol treatment throughout adulthood produced very minor fluctuations in neuroimmune genes, regardless of brain region. Intermittent “binge-type” ethanol during the adolescent period established an intermediate neuroinflammatory response in the hippocampus and frontal cortex, that can persist into adulthood. Chronic excessive drinking throughout adulthood, adolescent intermittent ethanol exposure, and thiamine deficiency all led to a loss of the cholinergic neuronal phenotype within the basal forebrain, reduced hippocampal neurogenesis, and alterations in the frontal cortex. Only thiamine deficiency results in gross pathological lesions of the thalamus. The behavioral impairment following these types of treatments is hierarchical: Thiamine deficiency produces the greatest impairment of hippocampal- and prefrontal-dependent behaviors, chronic ethanol drinking ensues mild impairments on both types of tasks and adolescent intermittent ethanol exposure leads to impairments on frontocortical tasks, with sparing on most hippocampal-dependent tasks. However, our preliminary data suggest that as rodents age following adolescent intermittent ethanol exposure, hippocampal functional deficits began to emerge. A necessary requirement for the advancement of understanding the neural consequences of alcoholism is a more comprehensive assessment and understanding of how excessive alcohol drinking at different development periods (adolescence, early adulthood, middle-aged and aged) influences the trajectory of the aging process, including pathological aging and disease.
Transgenerational transmission of an anticholinergic endophenotype with memory dysfunction
2017, Neurobiology of Aging
Citation Excerpt :
Although we observed a reduction in the number of ChAT expressing neurons in the F1 generation, the number of neurons expressing the NGFR p75 remained unchanged. This replicates our previous observation that the expression of the NGFR p75 is much less sensitive to the effects of ethanol than the expression of ChAT (Arendt et al., 1995). In conjunction with our results of the biochemical assays which show a reduced activity of ChAT in the basal forebrain, this likely indicates that cholinergic basal forebrain neurons remain unchanged in number while their ability to express ChAT is impaired.
Impaired cholinergic neurotransmission associated with cognitive dysfunction occurs in various mental disorders of different etiologies including Alzheimer's disease and postalcoholic dementia and others. To address the question whether there exists a common endophenotype with a defined genetic and/or epigenetic signature causing mental dysfunction in these disorders, we investigated 2 generations of offspring born to alcohol-treated mothers. Here, we show that memory impairment and reduced synthesis of acetylcholine occurs in both F1 (exposed to ethanol in utero) and F2 generation (never been exposed to ethanol). Effects in the F2 generation are most likely consequences of transgenerationally transmitted epigenetic modifications in stem cells induced by alcohol. This clearly documents the role of ancestral history of drug abuse on the brain development of subsequent generations. The results further suggest an epigenetic trait for an anticholinergic endophenotype associated with cognitive dysfunction which might be relevant to our understanding of mental impairment in neurodegenerative disorders such as Alzheimer's disease and related disorders.
Tau and tauopathies
2016, Brain Research Bulletin
Most neurodegenerative diseases are characterized by intracellular aggregates of insoluble proteins. As for the majority of these disorders, aetiology and pathogenesis are only poorly understood; current nosological concepts are largely based on these molecular signatures of protein aggregates which also provide valuable tools for neuropathological differential diagnosis. The microtubule associated protein tau is one of these proteins that form intracellular fibrillary deposits in neurons and glial cells of a large variety of disorders today collectively referred to as tauopathies. While dysfunction of tau has unequivocally been shown to be able to cause neurodegeneration, the precise mechanisms of how tau is involved in neurodegenerative disorders is still poorly understood. After research has focused for several decades on the axonal function of tau and on the fibrillar tau aggregation, more recent cell biological studies have opened up new insights into the role of tau at the synapse and in the nucleus. According to currently emerging cell biological concepts, tau might play a role in the regulation of neuronal plasticity in a wide array of neuronal networks. In addition, it might be involved in regulating genome stability. The most intriguing question relevant both to physiological and pathophysiological function of tau is the biological meaning of the large heterogeneity of isoforms of tau which apparently is a rather promiscuous molecule. The present review is divided into two parts. First, we give an overview on the molecular biology and cell biology of tau and its physiological functions. The second part deals with the pathophysiology of tau and description of tauopathies which comprise more than 20 disorders including Alzheimer's disease, progressive supranuclear palsy, cortico basal degeneration, Pick's disease and others.
Ethanol- and acetaldehyde-induced cholinergic imbalance in the hippocampus of Aldh2-knockout mice does not affect nerve growth factor or brain-derived neurotrophic factor
2013, Brain Research
Neurotrophins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), play an important role in the maintenance of cholinergic-neuron function. The objective of this study was to investigate whether ethanol (EtOH)- and acetaldehyde (AcH)- induced cholinergic effects would cause neurotrophic alterations in the hippocampus of mice. We used Aldh2 knockout (Aldh2-KO) mice, a model of aldehyde dehydrogenase 2 (ALDH2)-deficiency in humans, to examine the effects of acute administration of EtOH and the role of AcH. Hippocampal slices were collected and the mRNA and protein levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), NGF and BDNF were analyzed 30 min after the i.p. administration of EtOH (0.5, 1.0, or 2.0 g/kg). We show that treatment with 2.0 g/kg of EtOH decreased ChAT mRNA and protein levels in Aldh2-KO mice but not in wild-type (WT) mice, which suggests a role for AcH in the mechanism of action of EtOH. The administration of 2.0 g/kg of EtOH increased AChE mRNA in both strains of mice. EtOH failed to change the levels of NGF or BDNF at any dose. Aldh2-KO mice exhibited a distinctly lower expression of ChAT and a higher expression of NGF both at mRNA and protein levels in the hippocampus compared with WT mice. Our observations suggest that administration of EtOH and elevated AcH can alter cholinergic markers in the hippocampus of mice, and this effect did not change the levels of NGF or BDNF.

View all citing articles on Scopus

View full text

Degeneration of rat cholinergic basal forebrain neurons and reactive changes in nerve growth factor expression after chronic neurotoxic injury—I. Degeneration and plastic response of basal forebrain neurons

Abstract

Neurosci. Lett.

Neuroscience

Neurosci. Lett.

Neuroscience

Neuroscience

Neuroscience

Expl Neurol.

Neurosci. Lett.

Neurosci. Lett.

Neurobiol. Aging

Neurobiol Aging

Expl Neurol.

Expl Neurol.

Neuroscience

Neuroscience

Brain Res.

Brain Res.

Brain Res.

Devl Brain Res.

Brain Res.

Devl Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neuron

Molec. Brain Res.

Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

Neuroscience

Molec. Brain Res.

Brain Res.

Brain Res.

Biochem. biophys. Res. Commun.

Biochem. biophys. Res. Commun.

Expl Neurol.

Neurosci. Lett.

The cholinergic deafferentation of the cerebral cortex induced by chronic consumption of alcohol: reversal by cholinergic drugs and transplantation

Cholinergic-rich brain transplants reverse alcohol-induced memory deficits

Nature