Long-term environmental impact on object recognition, spatial memory, and reversal learning capabilities in Cacna1c haploinsufficient rats

Abstract

Genetic and environmental influences are thought to interact in their contribution to the etiology of major neuropsychiatric disorders. One of the best replicated findings obtained in genome-wide association studies are genetic variants in the CACNA1C gene. Here, we used our constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment during the critical juvenile developmental period to observe their long-term interactive effects with Cacna1c haploinsufficiency. Our study provides evidence for a gene x environment interaction, i.e. an interplay between Cacna1c haploinsufficiency and environment during juvenile development, on object recognition, spatial memory, and reversal learning capabilities. Social and physical enrichment had a positive influence on Cacna1c+/− rats and Cacna1c+/+ littermate controls on spatial and reversal learning, while post-weaning social isolation negatively affected novel object recognition in both genotypes. Despite intact spatial learning and re-learning abilities in all groups, slight but consistent deficits were evident in Cacna1c+/− rats previously housed under standard conditions particularly during reversal learning but not Cacna1c+/− rats previously exposed to social and physical enrichment. Together, this supports the notion that Cacna1c interacts with the environment to shape disease vulnerability and associated alterations in cognitive functioning.

Social Behavior and Ultrasonic Vocalizations in a Genetic Rat Model Haploinsufficient for the Cross-Disorder Risk Gene Cacna1c

“…Such effects were primarily seen in males but not females. Social and physical enrichment had positive effects in Cacna1c +/− rats and Cacna1c +/+ littermate controls and ameliorated slight reversal learning deficits displayed by Cacna1c +/− rats [14]. Novel object recognition memory was not affected by Cacna1c haploinsufficiency but impaired following post-weaning social isolation in both genotypes.…”

“…In a recent series of studies, we applied a genomically informed approach and contributed extensively to the behavioral characterization of a genetic rat model haploinsufficient for the cross-disorder risk gene Cacna1c [13][14][15][16][17][18][19], flanked by neurobiological analyses [20][21][22][23]. In this rat model, Cav1.2 expression in the brain is reduced to about 50% of wildtype littermate controls, both in males [15] and females [16].…”

Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 L-type voltage gated calcium channel subunit CACNB2

“…Thus, peripheral miR-499-5p expression, possibly as a result of early life adversity, is strongly upregulated in BD patients, further supporting a functional role of miR-499-5p in BD pathogenesis. To determine whether early life adversity also induced the expression of miR-499-5p in the brain, we exposed rats to juvenile social isolation with the aim to model physical and emotional neglect (Figure 1D), which is known to affect behaviors relevant for affective disorders, such as anxiety, drug addiction, and cognitive performance (40)(41)(42). As expected, socially isolated rats showed significantly lower hippocampal c-fos and Arc expression (Figure 1E and F), neural activity-induced genes which are known to be down-regulated upon social isolation in the rat hippocampus (43,44).…”

Environmental Enrichment Protects Against Cognition Deficits Caused by Sepsis-Associated Encephalopathy

“…The Novel Object Recognition Task (NORT) is a behavioral test that was developed to assess non-spatial working memory [38,39]. In the present study, this specific type of memory will be called "recognition memory".…”