Assistant Professor George Mason University, United States
Introduction:: In the hippocampal formation, cholinergic modulation supports the formation of spatial memories and cognitive functions that enable memory-guided navigation. In particular, cholinergic dynamics have been hypothesized to modulate brain states supporting either the learning or recall of spatial memories. The primary and major source of cholinergic innervation of the hippocampal formation is provided by cholinergic projection neurons in the medial septum and vertical diagonal band of Broca. However, little is known about the temporal dynamics in cholinergic modulation and how changes in cholinergic dynamics support changes in behavioral activities related to hippocampus-dependent learning or recall of spatial memories on behaviorally relevant timescales.
Materials and Methods:: In this study, we adopted a fiber-photometric approach to quantify temporal dynamics in the activity of cholinergic septo-hippocampal projection neurons on a sub-second timescale. The cholinergic activity was monitored in mice during a performance in an object location recognition memory task. We performed video tracking of exploratory behavioral activities of mice during the task using a deep learning approach. Object location recognition memory is a critical cognitive function that plays a pivotal role in an individual's ability to recall the location of objects in a particular environment. Previous studies have underscored the vital function of cholinergic neurons in animals and human subjects in the acquisition of memories, including object recognition memory. We conducted two trials in n >= 3 mice, each comprising two phases: learning and recall, separated by a 1-hour delay period. In the learning phase, we placed two identical objects in a square environment surrounded by walls and a local visual cue card (black acrylic box, 40 x 40 x 30 cm3); we allowed the mice to explore the environment and both objects at their respective locations for a fixed duration (15 minutes). Mice were placed back in their home cage during the delay period. For the recall phase, we relocated one of the objects within the box to a novel location near the opposite corner of the environment. In the recall phase, we placed mice back in the box and allowed them to explore for another fixed duration (15 minutes).
Results, Conclusions, and Discussions:: We evaluated object location recognition memory by measuring the difference in time mice spent exploring the identical objects at novel and familiar locations. Upon performing statistical analyses on the data collected during the experiments, we observed that mice spent significantly more time exploring the novel object location compared to the familiar object location. This finding remained consistent when analyzing data in individual mice. Here, we have adapted and applied an object location memory task on mice; we have shown that there is a novelty preference in the behavior of mice to react to changes in their environment. By using this task in combination with fiber photometry, we were able to investigate changes in cholinergic activity associated with exploratory activities and the learning and recall of object locations on a sub-second time scale. In this study, current analyses focus on evaluating the correlation between temporal dynamics in cholinergic activity and various exploratory behavioral activities during the object location recognition task.
Quantifying temporal dynamics in cholinergic modulation of exploratory activities during learning and recall of spatial memories could provide valuable insights into the neural basis of memory function. The expected will allow us to test the hypothesis that cholinergic activity is correlated to the encoding or acquisition of memory, while brain states associated with low levels of acetylcholine are associated with retrieving memory traces. This information enhances our comprehension of hippocampal circuits; We expect this knowledge to help contribute to identifying and developing novel treatment options for cognitive disorders associated with cholinergic dysfunction.
