Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism
Maria A. de Souza SilvaBernd LenzAndrea RotterTeresa BiermannOliver PetersAlfredo Ramı́rezFrank JessenWolfgang MaierMichael HüllJohannes SchröderLutz FrölichStefan TeipelOliver GruberJohannes KornhuberJoseph P. HustonChristian P. MüllerSandra Schäble
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Significance Cognitive decline during aging impairs life quality and may lead to dementia. It is associated with a dysfunction of the brain acetylcholinergic system. Here we demonstrate that pharmacological stimulation of neurokinin3 receptors improves learning and memory in aged rats by enhancing acetylcholinergic function in the brain. In a human association study we show that a single-nucleotide polymorphism in the neurokinin3-receptor–coding gene TACR3 can predict learning and memory in elderly patients with cognitive impairments and their hippocampus volume. These findings suggest the neurokinin3 receptor as a potential biomarker and treatment target for cognitive enhancement in the elderly.GABAergic interneurons appear to play a fundamental role in the functioning of the neostriatum by modulating the spiking of striatal projection neurons with great efficacy. The powerful and strongly divergent output of the GABAergic interneurons neurons suggests that modulation of their activity may be particularly effective at controlling the functioning of the entire neostriatal circuitry. Acetylcholine is one of the main modulators of striatal functioning. The effects of acetylcholine on fast-spiking (FS) GABAergic interneurons were studied with whole-cell recording in an in vitro slice preparation. Acetylcholine exerted two distinct effects on fast-spiking interneurons. Acetylcholine directly depolarized FS interneurons by acting on nondesensitizing soma-dendritic nicotinic receptors. In addition, acetylcholine attenuated the GABAergic inhibition of projection neurons by fast-spiking interneurons through activation of presynaptic muscarinic receptors. It is suggested that the nicotinic excitation of FS interneurons may play an important role in translating the effect of the brief behaviorally contingent cessation of firing of the tonically active cholinergic interneurons to the output neurons of the neostriatum. In contrast, the muscarinic presynaptic inhibitory mechanism may be engaged primarily during longer-lasting elevations of extracellular acetylcholine levels.
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Abstract Acetylcholine ( AC h) plays an important role in memory function and has been implicated in aging‐related dementia, in which the impairment of hippocampus‐dependent learning strongly manifests. Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus‐dependent learning, and the circuits involved. In addition, we will discuss the complexity of AC h actions in memory function to better understand the physiological role of AC h in memory. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms . image
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Summary Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses that, in turn, mediate inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs action shifting and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum where cholinergic interneurons are modulated by cholinergic neurons of the midbrain.
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Choline
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Nicotine is a strong psychoactive and addictive compound found in tobacco. Use of nicotine in the form of smoking, vaping or other less common methods during pregnancy has been shown to be related to poor health conditions, including cognitive problems, in babies and children. However, mechanisms of such cognitive deficits are not fully understood. In this study we analyzed hippocampus dependent cognitive deficits using a mouse model of developmental nicotine exposure. Pregnant dams were exposed to nicotine and experiments were performed in one month old offspring. Our results show that nicotine exposure did not affect locomotor behavior in mice. Hippocampus dependent working memory and object location memory were diminished in nicotine exposed mice. Furthermore, acetylcholine levels in the hippocampus of nicotine exposed mice were reduced along with reduced activity of acetylcholinesterase enzyme. Analysis of transcripts for proteins that are known to regulate acetylcholine levels revealed a decline in mRNA levels of high affinity choline transporters in the hippocampus of nicotine exposed mice but those of vesicular acetylcholine transporter, choline acetyltransferase, and α7-nicotinic acetylcholine receptors were not altered. These results suggest that developmental nicotine exposure impairs hippocampus dependent memory forms and this effect is likely mediated by altered cholinergic function.Published by Elsevier Inc. PMID: 34358612
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Acetylcholine has long been implicated in memory, including hippocampal-dependent memory, but the specific role for this neurotransmitter is difficult to identify in human neuropsychology. Here, we review the evidence for a mechanistic model of acetylcholine function within the hippocampus and consider its explanatory power for interpreting effects resulting from both pharmacological anticholinergic manipulations and lesions of the cholinergic input to the hippocampus in animals. We argue that these effects indicate that acetylcholine is necessary for some, but not all, hippocampal-dependent processes. We review recent evidence from lesion, pharmacological and electrophysiological studies to support the view that a primary function of septohippocampal acetylcholine is to reduce interference in the learning process by adaptively timing and separating encoding and retrieval processes. We reinterpret cholinergic-lesion based deficits according to this view and propose that acetylcholine reduces the interference elicited by the movement of salient locations between events.
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Nicotine is a strong psychoactive and addictive compound found in tobacco. Use of nicotine in the form of smoking, vaping or other less common methods during pregnancy has been shown to be related to poor health conditions, including cognitive problems, in babies and children. However, mechanisms of such cognitive deficits are not fully understood. In this study we analyzed hippocampus dependent cognitive deficits using a mouse model of developmental nicotine exposure. Pregnant dams were exposed to nicotine and experiments were performed in one month old offspring. Our results show that nicotine exposure did not affect locomotor behavior in mice. Hippocampus dependent working memory and object location memory were diminished in nicotine exposed mice. Furthermore, acetylcholine levels in the hippocampus of nicotine exposed mice were reduced along with reduced activity of acetylcholinesterase enzyme. Analysis of transcripts for proteins that are known to regulate acetylcholine levels revealed a decline in mRNA levels of high affinity choline transporters in the hippocampus of nicotine exposed mice but those of vesicular acetylcholine transporter, choline acetyltransferase, and α7-nicotinic acetylcholine receptors were not altered. These results suggest that developmental nicotine exposure impairs hippocampus dependent memory forms and this effect is likely mediated by altered cholinergic function.
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