Gene-experience interaction alters the cholinergic septohippocampal pathway of mice

Spatial learning requires the septohippocampal pathway. The interaction of learning experience with gene products to modulate the function of a pathwa y may underlie use-dependent plasticity. The regulated release of nerve gro wth factor (NGF) from hippocampal cultures and hippocampus, as well as its actions on cholinergic septal neurons, suggest it as a candidate protein to interact with a learning experience. A method was used to evaluate NGF gen e-experience interaction on the septohippocampal neural circuitry in mice. The method permits brain region-specific expression of a new gene by using a two-component approach: a virus vector directing expression of cre recomb inase; and transgenic mice carrying genomic recombination substrates render ed transcriptionally inactive by a "floxed" stop cassette. Cre recombinase vector delivery into transgenic mouse hippocampus resulted in recombination in 30% of infected cells and the expression of a new gene in those cells. To examine the interaction of the NGF gene and experience, adult mice carry ing a NGF transgene with a flexed stop cassette (NGFXAT) received a cre rec ombinase vector to produce localized unilateral hippocampal NGF gene expres sion, so-called "activated" mice. Activated and control nonactivated NGFXAT mice were subjected to different experiences: repeated spatial learning, r epeated rote performance, or standard vivarium housing. Latency, the time t o complete the learning task, declined in the repeated spatial learning gro ups. The measurement of interaction between NGF gene expression and experie nce on the septohippocampal circuitry was assessed by counting retrogradely labeled basal forebrain cholinergic neurons projecting to the hippocampal site of NGF gene activation. Comparison of all NGF activated groups reveale d a graded effect of experience on the septohippocampal pathway, with the l argest change occurring in activated mice provided with repeated learning e xperience. These data demonstrate that plasticity of the adult spatial lear ning circuitry can be robustly modulated by experience-dependent interactio ns with a specific hippocampal gene product.