Abstract
Activated neurons express immediate-early genes, such as Arc. Expression of Arc in the hippocampal granule cell layer, an area crucial for spatial learning and memory, is increased during acquisition of spatial learning; however, it is unclear whether this effect is related to the task-specific learning process or to nonspecific aspects of the testing procedure (e.g. exposure to the testing apparatus and exploration of the environment). Herein, we show that Arc-positive cells numbers are increased to the same extent in the granule cell layer after both acquisition of a single spatial learning event in the active place avoidance task and exploration of the testing environment, as compared to naïve (i.e. caged) mice. Repeated exposure the testing apparatus and environment did not reduce Arc expression. Furthermore, Arc expression did not correlate with performance in both adult and aged animals, suggesting that exploration of the testing environment, rather than the specific acquisition of the active place avoidance task, induces Arc expression in the dentate granule cell layer. These findings thus suggest that Arc is an experience-induced immediate-early gene.
Highlights
Immediate-early genes (IEGs) are rapidly and transiently upregulated in neurons activated by physiological and supraphysiological stimuli, such as behavioral experience or high-frequency stimulation[1,2,3]
Several questions remain unanswered: Is Arc expression selectively upregulated in the hippocampus following acquisition of spatial learning? And, if so, is such an effect localized to a specific hippocampal cell subpopulation? The study presented aimed to answer these questions; to do so, we utilized the active place avoidance (APA) task with a novel control condition; mice could freely explore the testing environment with the shock zone turned off (i.e. ‘exposure only control group’ = Exp Ctrl), which addresses many of the aspects of behavioral testing unable to be tested under caged conditions
As Arc mRNA levels remain elevated in dentate granule cells for at least 8 hours after spatial exploration[15], and Arc protein is required for both the induction and consolidation of long-term potentiation[1,5,6,7,8,9,10], we explored whether differences in Arc protein expression between experimental groups did emerge at later stages for the condition with the critical and more salient learning, i.e. the APA task
Summary
Immediate-early genes (IEGs) are rapidly and transiently upregulated in neurons activated by physiological and supraphysiological stimuli, such as behavioral experience or high-frequency stimulation[1,2,3]. The current prevailing model is that immature granule cells, which are more excitable and more amenable to synaptic plasticity than their mature counterparts, influence the activity (and IEG expression) of the mature granule cells by differentially modulating inhibitory interneurons and excitatory mossy cells[21,22,23,24,25] Consistent with this possibility, Guzowski and colleagues reported that after acquisition of the Morris water maze task, Arc mRNA levels in the whole dorsal hippocampus positively correlated with performance in the task; a correlation between task performance and Arc expression in specific hippocampal subregions could not be determined due to limited spatial resolution[3]. Arc+ granular cells are upregulated shortly after introduction to a new environment, suggesting that somatic Arc expression may be a generalized experience-induced marker of deprivation, rather than a specific reporter of goal-directed spatial learning These findings address several gaps in our understanding as to how induction of somatic Arc expression in hippocampal neurons relates to the acquisition of spatial learning as opposed to exploration. We have examined the spatial learning performance of aged 25-month-old animals, and its relationship to somatic Arc expression
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