Genetic Differences in Dorsal Hippocampus Acetylcholinesterase Activity Predict Contextual Fear Learning Across Inbred Mouse Strains

Abstract

Learning is a critical behavioral process that is influenced by many neurobiological systems. We and others have reported that acetylcholinergic signaling plays a vital role in learning capabilities, and it is especially important for contextual fear learning. Since cholinergic signaling is affected by genetic background, we examined the genetic relationship between activity levels of acetylcholinesterase (AChE), the primary enzyme involved in the acetylcholine metabolism, and learning using a panel of 20 inbred mouse strains. We measured conditioned fear behavior and AChE activity in the dorsal hippocampus, ventral hippocampus, and cerebellum. Acetylcholinesterase activity varied among inbred mouse strains in all three brain regions, and there were significant inter-strain differences in contextual and cued fear conditioning. There was an inverse correlation between fear conditioning outcomes and AChE levels in the dorsal hippocampus. In contrast, the ventral hippocampus and cerebellum AChE levels were not correlated with fear conditioning outcomes. These findings strengthen the link between acetylcholine activity in the dorsal hippocampus and learning, and they also support the premise that the dorsal hippocampus and ventral hippocampus are functionally discrete.

Loss of GABA co-transmission from cholinergic neurons impairs behaviors related to hippocampal, striatal, and medial prefrontal cortex functions

“…Disturbances in ACh signaling in neurons or glia in the hippocampus, amygdala, and mPFC were found in cue encoding, spatial processing, aversive learning, extinction, and fear renewal (Lotfipour et al, 2013 , 2017 ; Kutlu et al, 2018 ; Likhtik and Johansen, 2019 ; Titus et al, 2019 ; Chen et al, 2020 ; Kellis et al, 2020 ; Mineur et al, 2020 ; Oliveros-Matus et al, 2020 ; Miguelez Fernandez et al, 2021 ; Mooney-Leber et al, 2021 ; Zhang et al, 2021 ; Yanpallewar et al, 2022 ). For example, feed-forward inhibition from the ventral hippocampus to PL is sufficient to decrease contextual fear renewal, while feed-forward inhibition from the ventral hippocampus to IL increases fear renewal (Marek et al, 2018 ; Vasquez et al, 2019 ).…”

Loss of GABA co-transmission from cholinergic neurons impairs behaviors related to hippocampal, striatal, and medial prefrontal cortex functions

“…Disturbances in ACh signaling in neurons or glia in hippocampus, amygdala and mPFC were found in cue encoding, spatial processing, aversive learning, extinction, and fear renewal (Likhtik and Johansen (2019), Yanpallewar et al (2022), Zhang et al (2021), Lotfipour et al (2013), Lotfipour et al (2017), Kutlu et al (2018), Titus et al (2019), Mineur et al (2020), Chen et al (2020), Mooney-Leber et al (2021), Kellis et al (2020), Yanpallewar et al (2022), Miguelez Fernandez et al (2021), Oliveros-Matus et al (2020)). For example, feed-forward inhibition from the ventral hippocampus to PL is sufficient to decrease contextual fear renewal, while feed-forward inhibition from ventral hippocampus to IL increases fear renewal (Marek et al (2018), Vasquez et al (2019)).…”