How genes and the environment influence executive cognitive functions in inbred strains of mice

Deficits in working memory and attention are endophenotypes of major mental disorders, including schizophrenia and mood disorders. Such executive cognitive dysfunctions can also be triggered by early life stress (ELS)... [ view full abstract ]

Deficits in working memory and attention are endophenotypes of major mental disorders, including schizophrenia and mood disorders. Such executive cognitive dysfunctions can also be triggered by early life stress (ELS) exposure of laboratory mice. However, the emergence of such deficits depends upon their genetic background. For example, while the stress susceptible strain Balb/c exhibits spatial working memory and extradimensional attention set-shifting deficits after ELS (infant maternal separation for 3 h daily from postnatal age P2 until P15), the more resilient strain C57Bl/6 does not exhibit such deficits. In addition to genetic factors that differentially modulate the stress susceptibility in these two strains, our studies showed that the emergence of cognitive deficits in Balb/c mice is linked to an ELS-triggered epigenetic response, namely reduced activity of histone deacetylase 1 (HDAC1) and increased histone H4K12 acetylation at promotors of distinct plasticity-associated genes that are known to modulate cognitive task performance. As a result, cognitive test exposure triggers enhanced recruitment of RNA polymerase II to these promotors and, thereby, abnormally increases test-induced transcription of genes that influence cognitive task performance negatively. This epigenetic mark of ELS exposure is transmitted to the first progeny of Balb/c mothers, and the male and female progeny (although not exposed to ELS) exhibits the same epigenetic and cognitive abnormalities. Our studies showed that this transmission is germ-line independent and triggered by maternal behavior¹. Moreover, this trans-generational effect exerted by ELS Balb/c mothers on the cognitive phenotypes of their offspring also extends to different genetic backgrounds. F1 C57Bl/6 x Balb/c hybrid mice that were raised by Balb/c mothers during ELS exposure develop the same cognitive phenotypes found in Balb/c mice², and C57Bl/6 foster pups develop deficits in attention-set-shifting (but not working memory)³. In all strains of pups, reduced promotor-associated HDAC1 activity is a common underlying mechanism for these deficits, but the genes affected differ: While in Balb/c mice, test-induced overexpression of brain-derived neurotrophic factor (Bdnf) transcript variant 3 is responsible for the emergence of cognitive deficits, foster C57Bl/6 mice exhibit normal Bdnf expression but increased test-induced expression of the early growth response gene 2 (Egr 2), and F1 hybrid mice exhibit both increased Bdnf and Egr 2 expression^2,3. These findings indicate that the magnitude of ELS effects on pups depend upon their genetic background and their environment (maternal care).  Nevertheless, a pharmacological intervention that lowered the levels of acH4K12 during adolescent development (P35 to P59) in ELS Balb/c mice significantly improved their cognitive functions, and abolished the trans-generational propagation of such deficits¹.   

References:

• Schmauss C, Lee-McDermott Z, Ramos Medina, L (2014) Trans-generational effects of early life stress: The role of maternal behavior. Sci Rep 4:4873; DOI:10.1038/srep04873(2014).
• Feifel AJ, Shair HN, Schmauss C (2017) Behavioral and epigenetic responses to early life stress in mice: The role of maternal behavior and the genetic background of pups. Genes Brain Behav 83: 63-71.  doi: 10.1111/gbb.12395.
• Adler SM, Schmauss C (2016) Cognitive deficits triggered by early life stress: The role of histone deacetylase 1. Neurobiol Dis Oct;94:1-9. doi: 10.1016/j.nbd.2016.05.018.