Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

Abstract

Objective . Investigate whether the disruption of normal hippocampal rhythms via optogenetic stimulation of the medial septum (MS) during late postnatal development has enduring effects on the allocentric memory of rat pups. Methods . Hippocampal theta oscillations were non-endogenously regulated in rat pups using blue light (465-nm) pan-neuronal optogenetic activation of the MS from postnatal day (P)21–25 using random sinewave frequencies ranging from 0.5 to 110 Hz. Non-stimulated and yellow light (590-nm) stimulated rats were used as controls, and local field potentials from the hippocampus and MS were recorded unilaterally during stimulations. In early adulthood, spatial cognition was assessed using the active avoidance task. Rats were perfused and tissue containing the MS and hippocampus was harvested and sectioned to assess cell density. Power spectrum density of both the MS and hippocampus; coherence, and voltage correlation analysis between both structures were used to compare baseline to the disruptive stimulation. Results . During late postnatal development, non-selective optogenetic activation of the MS tightly regulated hippocampal oscillations. Disruptive stimulation increased power but reduced coherence and voltage correlations; and resulted in impaired spatial learning compared with controls. Impairment of spatial cognition was not attributed to MS or hippocampal cell loss. Conclusions. These results demonstrate that hippocampal oscillations can be precisely regulated with non-selective optogenetic stimulation of the MS in weanling rats. A disruptive hippocampal stimulation protocol during the critical period of memory development results in long-standing spatial cognitive deficits that is not attributed to cell loss. Significance . Disruptive activity during postnatal development, such as occurs during early life seizures, has complex effects on developing neural circuits relevant to cognition. By mimicking disruption of MS-hippocampal entrainment in an isolated fashion, it may be possible to pinpoint mechanisms through which ELS may affect cognition.