Correlation between choline acetyltransferase activity and learning ability in different mice strains and their offspring

doi:10.1016/0006-8993(74)90650-7

Brain Research

Volume 72, Issue 1, 31 May 1974, Pages 65-70

https://doi.org/10.1016/0006-8993(74)90650-7 Get rights and content

Abstract

The enzymes related to acetylcholine metabolism were investigated in several cortical regions of 3 inbred strains of mice (SEC, DBA and C57) differing in learning ability, and in their F1 offsprings. A higher choline acetyltransferase (ChAc) activity was found in the temporal lobe of mice with high learning ability (SEC and DBA) than in C57 mice which score poorly. The genetic behavioural analysis conducted on the F1 offsprings of these strains¹⁸ demonstrated that F1 hybrids of SEC and C57 crosses were able to reach the same high learning levels as the parental SEC strain. In contrast, the DBA × C57 offsprings performed as poorly as the C57 strain which had low levels of performance. We showed that ChAc activity in the temporal lobe of the SEC × C57 hybrids was close to that of the SEC strain and in the F1 offspring of DBA × C57 crosses, near the values of the parental line C57.

It was suggested that these differences may constitute a neurochemical correlate of the differences in learning abilities of these mice strains.

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We considered two of the most common strains in use for developing transgenic or knock-out mice models of AD: DBA/2J (from now on indicated as DBA) and C57BL/6J (from now on indicated as C57), which show behavioral differences in terms of memory and learning test (Kim et al., 2019). Previous examinations of learning differences in C57 and DBA mice linked to biochemical regulation have largely focused on the cholinergic system (Ammassari-Teule and Caprioli, 1985; Mandel et al., 1974; Pick and Yanai, 1989; Upchurch and Wehner, 1988, 1987). However, strong differences between the two strains in acetylcholinesterase and choline acetyltransferase activities have been reported in cortical regions (Schwab et al., 1990), which may contribute to performances in cognitive tests where somatosensitive functions are involved.
The cholinergic neurotransmitter system in the brain is crucial in processing information related to cognitive, behavioral, and motor functions. A cholinergic dysfunction has been correctly described as one of the primary causes of neurodegenerative diseases. Differences in levels of acetylcholine or expression and function of receptors in selected brain areas have been indicated as one of the causes of sexual dimorphism in neurotransmission. However, variability in results among studies based on different mice strains could affect conclusions on this topic. Visual evoked potentials (VEPs) of male and female DBA/2J and C57BL/6J mice, which are two of the most common strains backgrounds in use for developing transgenic mice models of neurological diseases, have been studied. Effects induced by a single low dose of physostigmine have also been performed to evaluate the cholinergic system involvement. VEPs responses to luminous stimuli in C57BL/6J mice have shown a consistently lower latency than in DBA/2J, confirming the previous observation of strain differences in cholinergic function. Interestingly, strains present an opposite-sex difference in VEP latency not apparently related to sensitivity to physostigmine. These findings point at paying extreme attention to the choice of the genetic background of the animal model, especially in those basic and pre-clinical experiments that involve visual functioning.
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Inter-strain genetic heterogeneity and the histological and endocrinological variables are often considered to be the mediator of the strain-to-strain endophenotypic variances in mice. The inter-strain variability reflected in the sizes of the hippocampus [13], nucleus accumbens [14] and neocortical elements [15], as well as the diversities in the cholinergic [16] and dopaminergic [17] feedbacks could contribute to social and cognitive plasticity [18,19]. Hence, the present study is focused on characterizing the contributions of genetic heterogeneity and environmental challenges in developing PTSD-like features elicited by an agonistic social situation including both threat and attack.
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Mouse models of feeding provide a useful tool for elucidating the molecular pathways of energy regulation. The majority of studies in mice have been limited to intake analyses conducted over extended periods of time, which fail to distinguish between a variety of factors that influence nutrient intake. Using licking microstructure analyses we examined both the size and number of licking bursts for water, polycose, sucrose and lecithin in three strains of mice (C57BL/6J, 129Sv/ImJ and C57129F1 hybrids), using pause criteria (250–500, >500 and >1000 ms) that have previously been described in the rat. Burst size and number varied both as a function of tastant concentration and mouse strain; however, these differences were most evident with the >1000 ms pause criterion. Consistent with previous reports, during water consumption C57 mice showed longer mean interlick intervals, a larger number of bursts but reduced burst size relative to the two other strains. F1 mice showed larger burst sizes for polycose, while C57 mice displayed a greater number of bursts for both polycose and sucrose. Both 129 and F1 mice were insensitive to sucrose concentration, whereas C57 mice showed attenuated lecithin intake influenced by a reduction in the size of bursts for this tastant. These results suggest that these strains of mice display differences in the pattern of licking that are most evident with the use of larger pause criteria. These differences in licking behavior might reflect influences of genetic background on pre- and post-ingestive factors controlling intake, the reinforcing properties of each tastant, or native differences in licking style.
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The effects of the cholinomimetic drug, physostigmine (0, 0.01, 0.025, 0.05 and 0.1 mg/kg, i.p.), on shuttle-box avoidance learning and electroencephalographic (EEG)activity were investigated, in two separate studies, in mice belonging to the inbred C57BL/6 (C57) and DBA/2 (DBA) strains. The results of the behavioral investigation showed a consistent, significant enhancement of avoidance performance, on the whole of 5 daily training sessions, in C57 mice treated with the lowest dose (0.01 mg/kg) and in DBA mice treated with the highest doses (0.05 and 0.1 mg/kg) of the drug. Doses higher than 0.01 mg/kg, in C57 mice, and lower than 0.05 mg/kg, in DBA mice, had no significant effect. The avoidance improvements induced by physostigmine cannot be ascribed to a general behavioral activation, since the doses that increased avoidance responses did not affect or even depressed spontaneous locomotor activity. The same doses of treatment which increased avoidance responding, also induced, in the same strains, consistent enhancement of 4–7 Hz (theta) EEG band power and decrease of 7–12 Hz (alpha) band power. Results suggest that the effects induced by physostigmine on the EEG and on the shuttle-box performance of mice are related to the same neurochemical systems, and are dependent upon the interaction of the dose with specific strain sensitivity.
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One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of α-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal α-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal α-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane α-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal α-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that α-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.
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Single neuron activity in the monkey amygdala was investigated during cue signalled conditioned bar press feeding behavior and the effects of electrophoretically applied acetylcholine (ACh) and atropine were analyzed. ACh increased the firing rate of one third of the neurons tested; these excitatory responses were inhibited by the muscarinic receptor antagonist atropine. No characteristic location of ACh-sensitive neurons was found, cells were diffusely distributed throughout the amygdala. Activity of ACh-sensitive neurons did not correlate with any particular event during the bar press feeding task. However, continuous application of ACh at low current intensity during the task significantly enhanced the task-related excitatory firing patterns, or markedly attenuated the inhibitory responses. Continuous application of atropine elicited or enhanced inhibitory response patterns. These results suggest that the cholinergic system of the monkey amygdala facilitates neuronal excitation but attenuates inhibition related to various phases of feeding behavior, such as to cue recognition, food aquisition and rewarding process.

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Correlation between choline acetyltransferase activity and learning ability in different mice strains and their offspring

Abstract

Brain Research

Brain Research

Comp. gen. Pharmacol.

J. biol. Chem.

Genetic aspects in learning and memory in mice

Science

The cholinergic synapse and the site of memory

Science

Comparison of acetylcholinesterase and choline acetyltransferase in temporal cortex of DBA and C57 mice

Nature New Biol.

Elicitation and inhibition of competitive fighting in food deprived mice

J. genetic Psychol.

Microdetermination of choline acetyltransferase—A comparison of Reineckevs. periodide precipitation

J. Neurochem.