Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory

Abstract

Deep brain stimulation (DBS)is an established therapeutic modality for the treatment of movement disorders and an emerging therapeutic approach for the treatment of disorders of mood and thought. For example, recently we have shown that DBS of the fornix may ameliorate cognitive decline associated with dementia. However, like other applications of DBS, the mechanisms mediating these clinical effects are unknown. As DBS modulates neurophysiological activity in targeted brain regions, DBS might influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters analogous to clinical high-frequency DBS, here we addressed this question in mice. We found that acute stimulation of the entorhinal cortex (EC) transiently promoted proliferation in the dentate gyrus (DG). Cells generated as a consequence of stimulation differentiated into neurons, survived for at least several weeks, and acquired normal dentate granule cell (DGC) morphology. Importantly, stimulation-induced promotion of neurogenesis was limited to the DG and not associated with changes in apoptotic cell death. Using immunohistochemical approaches, we found that, once sufficiently mature, these stimulation-induced neurons integrated into hippocampal circuits supporting water-maze memory. Finally, formation of water-maze memory was facilitated 6 weeks (but not 1 week) after bilateral stimulation of the EC. The delay-dependent nature of these effects matches the maturation-dependent integration of adult-generated DGCs into dentate circuits supporting water-maze memory. Furthermore, because the beneficial effects of EC stimulation were prevented by blocking neurogenesis, this suggests a causal relationship between stimulation-induced promotion of adult neurogenesis and enhanced spatial memory.

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

“…Lowering corticosterone secretion from midlife (Montaron et al 2006) or a midlife vitamin A supplementation (Touyarot et al 2013) for the rest of the animal's life prevents age-related spatial memory deficits and age-related decline in neurogenesis. In a young subject, pharmacological approaches, consisting of peripheral treatment with the cognitive enhancer ginseng (Qiao et al 2005), the peptidergic drug P21 (Li et al 2010), the histone acetyltransferases CBP/p300 (Chatterjee et al 2013), hippocampal gene transfer of VEGF (Cao et al 2004), blockade of NR2B-containing NMDAR (Hu et al 2008), stimulation of entorhinal cortex (Stone et al 2011a), or deletion of Toll-like receptors (TLRs) (Okun et al 2010), all promoted adult neurogenesis and facilitated memory performances in different learning tasks (contextual fear-conditioning paradigm, associative passive avoidance, and water maze).…”

Acute high frequency stimulation of the prefrontal cortex or nucleus accumbens does not increase hippocampal neurogenesis in rats

“…In Study 1, 5-bromo-2′deoxyuridine (BrdU; Sigma) was injected on post-stimulation day 3 (50 mg/kg every 6 h for 24 h) and animals were sacrificed the next day, as previously described (Encinas et al, 2011;Hamani et al, 2011;Stone et al, 2011;Toda et al, 2008). In Study 2, BrdU was given from post-stimulation days 3-5 (50 mg/kg every 6 h) and animals were sacrificed 28 days later.…”

“…In rodents, DBS increases levels of hippocampal serotonin (Adachi et al, 2005;Hamani et al, 2010b) and brain derived neurotrophic factor (Gersner et al, 2010;. In a recent series of studies, stimulation of limbic structures (Encinas et al, 2011;Hamani et al, 2011;Stone et al, 2011;Toda et al, 2008) or the Acb (Schmuckermair et al, 2013) has been shown to increase hippocampal neurogenesis. As the vmPFC has direct and indirect connections with the hippocampus (Vertes, 2004(Vertes, , 2006, it is conceivable to hypothesize that treatments that modulate its activity (e.g.…”

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

“…Application of acute high-frequency DBS in hippocampus EC of mice could lead to a transiently promoted proliferation in the dentate gyrus (DG) [142], and these DBS-induced neurons merged with hippocampal circuits once they were mature.…”