scholarly journals Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071

2019 ◽  
Author(s):  
Aaron Kucinski ◽  
Kyra B. Phillips ◽  
Ajeesh Koshy Cherian ◽  
Martin Sarter
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Acetylcholinesterase Inhibitors ◽  
Female Rats ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Drug Induced ◽  
Attention Task ◽  
Age Related ◽  
Attentional Performance

AbstractLoss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and to impairments in gait and balance, and the resulting risks for falls, in patients with Parkinson’s disease (PD). Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. Here we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that an M1 PAM amplifies such transient signaling, thereby enhancing and rescuing attentional performance. Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period assessing their capacity for recovering performance. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance recovery. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, and also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d’) in lesioned rats and facilitated the adoption of a more liberal response bias (B”D) in all female rats. Collectively, these findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.

scholarly journals Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071

2019 ◽  
Vol 237 (1) ◽  
pp. 137-153 ◽  
Author(s):  
Aaron Kucinski ◽  
Kyra B. Phillips ◽  
Ajeesh Koshy Cherian ◽  
Martin Sarter
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Attentional Performance

scholarly journals Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Ashley M. Fortress ◽  
Mona Buhusi ◽  
Kris L. Helke ◽  
Ann-Charlotte E. Granholm
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Memory Impairments ◽  
Age Related ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Cholinergic Degeneration ◽  
And Function ◽  
Do So

Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the firstin vivoevidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

scholarly journals Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

2009 ◽  
Vol 102 (4) ◽  
pp. 2194-2207 ◽  
Author(s):  
David Murchison ◽  
Angelika N. McDermott ◽  
Candi L. LaSarge ◽  
Kathryn A. Peebles ◽  
Jennifer L. Bizon ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Cognitive Status ◽  
Cognitively Impaired ◽  
Aged Rats ◽  
Middle Aged ◽  
Cholinergic Basal Forebrain ◽  
Age Related ◽  
Forebrain Neurons ◽  
Firing Properties

Alterations in neuronal Ca2+ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca2+ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca2+ current recording with Ca2+-sensitive ratiometric microfluorimetry to measure Ca2+ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age- or cognition-related changes in the amplitudes or fractional compositions of the whole cell Ca2+ channel currents. However, Ca2+ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca2+ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca2+ buffering by cholinergic basal forebrain neurons may be important during aging.

scholarly journals Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Debora Cutuli ◽  
Eugenia Landolfo ◽  
Annalisa Nobili ◽  
Paola De Bartolo ◽  
Stefano Sacchetti ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Basal Forebrain ◽  
Brain Aging ◽  
Life Quality ◽  
Cholinergic Neurons ◽  
Hippocampal Neurogenesis ◽  
Omega 3 ◽  
Pufa Supplementation ◽  
Aged Mice ◽  
Age Related

Abstract Background In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer’s disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology. Methods Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out. Results The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities. Conclusions The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD.

Age-related loss of calbindin from human basal forebrain cholinergic neurons

Neuroreport ◽  
1997 ◽  
Vol 8 (9) ◽  
pp. 2209-2213 ◽  
Author(s):  
Chuang-Kuo Wu ◽  
M-Marsel Mesulam ◽  
Changiz Geula
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Basal Forebrain Cholinergic Neurons ◽  
Age Related

Effects of Estradiol on Basal Forebrain Cholinergic Neurons and Their Impact on Cognitive Performance and Age-Related Cognitive Decline

2020 ◽  
pp. 282-302
Author(s):  
Robert B. Gibbs
Keyword(s):  
Estrogen Receptor ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Basal Forebrain ◽  
Essential Role ◽  
Cholinergic Neurons ◽  
Age Related ◽  
Estrogen Effects ◽  
Age Related Cognitive Decline ◽  
Cholinergic Projections

Cholinergic neurons in the basal forebrain play an important role in modulating wakefulness, alertness, and selective attention and contribute significantly to learning and memory processes. These neurons also are affected by estrogens. Loss of circulating estrogens negatively impacts the functionality of cholinergic projections to the hippocampus and cerebral cortex, resulting in impaired cognitive performance. These effects can be reversed by appropriate estrogen treatment or treatment with selective estrogen receptor agonists. Evidence also suggests that the cholinergic neurons play an essential role in enabling effects of estrogens on synaptic plasticity, which benefit cognitive performance. This chapter summarizes evidence for estrogen effects on basal forebrain cholinergic projections and the relevance of these findings to the maintenance of cognitive performance and to the prevention of age- and disease-related cognitive decline in women.

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