Basic Science and Pathogenesis.

Background: DNA microarray-based studies report differentially methylated positions (DMPs) in blood between cognitively unimpaired persons (CU) and persons with late-onset dementia due to Alzheimer's disease (AD) or Mild Cognitive Impairment (MCI) but interrogate less than 4% of the human genome. Whole genome methylation sequencing (WGMS) quantifies DNA methylation levels across the entire human genome (>25 million CpG loci). Using WGMS, we previously reported 28,038 DMPs within 2,707 genes between persons with and without AD.

Folate-mediated transgenerational inheritance of sperm DNA methylation patterns correlate with spinal axon regeneration.

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny.

Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels regulate neuronal excitability and represent a possible therapeutic target for major depressive disorder (MDD). These channels are regulated by intracellular cyclic adenosine monophosphate (cAMP). However, the relationship between cAMP signaling and the influence of HCN channels on behavior remains opaque.