RT Journal Article
SR Electronic
T1 Optogenetic entrainment of the septo-hippocampal circuit is state conditional and attenuates spatial accuracy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 392050
DO 10.1101/392050
A1 Philippe R. Mouchati
A1 Gregory L. Holmes
A1 Michelle L. Kloc
A1 Jeremy M. Barry
YR 2019
UL http://biorxiv.org/content/early/2019/01/10/392050.abstract
AB The manipulation of pattern generators in order to impose temporal organization on target nodes while accounting for dynamic changes in behavior and cognitive demand remains a significant challenge for the use of neurostimulation as a therapeutic treatment option. While perturbation through optogentic stimulation can reveal circuit mechanisms that create and locally integrate temporal organization, it is unclear whether superseding endogenous signals with artificial oscillations would benefit or impede hippocampus-dependent cognition or how cognitive demand might affect artificial septo-hippocampal entrainment. Optogenetic MS stimulation in wild-type rats in 3 conditions showed that septal input is more likely to supersede endogenous hippocampal LFP oscillations when animals are at rest or performing a hippocampus-dependent spatial accuracy task. Stimulation during a hippocampus-independent task, however, resulted in compensatory endogenous oscillations. Although stimulation effects on the inter-spike interval of hippocampal pyramidal cells mirrored task-conditional theta entrainment of the LFP, place field properties were unaffected. Analyses of spatial behavior indicate that optogenetic stimulation can attenuate performance and specific measures of goal zone estimation accuracy but otherwise does not affect the rat’s ability to navigate to the target quadrant. The results suggest that the behavioral effect of temporally organizing the septo-hippocampal circuit relative to an artificial theta signal is limited to the accuracy of the rat’s approximation of the goal zone location. These results have significant implications for the therapeutic use of optogenetic stimulation as a means of attenuating cognitive deficits associated with temporal discoordination.Author ContributionsJ.M.B designed the experiments and analyzed the data; P.R.M and J.M.B collected data; M.L.K. analyzed histological and Immunohistochemistry data. All authors wrote the paper.We are very appreciative of the thoughts on analysis and the interpretation of our results provided by Dr. Kamran Diba, Dr. Colin Lever, Dr. Matt Wilson, Dr. Nathan Insel, Dr. Andre Fenton, Dr. Allan Gulledge and the assigned anonymous reviewers. We thank Andrew Alvarenga (GMW) for assistance with the custom design and manufacture of optical and electrophysiological implants. We thank Bruno Rivard, Rhys Niedecker for assistance with components of Figure 1. We are grateful for COBRE support from Sheryl White who greatly assisted with immunohistochemistry and from Todd Classon who assisted with imaging. We thank Pierre-Pascal Lenck-Santini, Sylvain Barriere and Sophie Sakkaki for assistance with Matlab code used for signal processing. We thank Mr. Daniel Mills for editing. We also acknowledge Neuralynx (Montana, USA) for dedicated technical support and Karl Deisseroth for supplying the adenovirus used in the study. This work would not have been possible without the advice of Dr. John Kubie during development and implementation of the spatial accuracy task. We declare no conflicts of interest. This work was supported by startup funds to JMB by UVM and by the NIH Grants NS108765 (GLH/JMB); NS108296 (GLH/JMB).