Holmes, G. L. | bioRxiv Science

bioRxiv2018

State conditional optogenetic entrainment of the septo-hippocampal circuit reveals the importance of endogenous theta oscillations as a unit of spatial metric

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 rats 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 rats 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.

neuroscience↗

bioRxiv2017

Environmental Enrichment Normalizes Hippocampal Timing Coding in a Malformed Hippocampus

Neurodevelopmental insults such as malformations of cortical development (MCD) are a common cause of psychiatric disorders, learning impairments and epilepsy. Animals with MCDs have impairments in spatial cognition that, remarkably, are improved by post-weaning environmental enrichment (EE). To establish the network-level mechanisms responsible for these impacts, hippocampal in vivo single unit recordings were performed in freely moving animals in an open arena. We took a generalized linear modeling approach to extract fine spike timing (FST) characteristics and related these to place cell fidelity used as a surrogate of spatial cognition. We find that MCDs disrupt FST and place-modulated rate coding in hippocampal CA1 and that EE restores both to normal. Moreover, FST parameters predict spatial coherence of neurons, suggesting that mechanisms determining FST are critical for cognition. This suggests that FST parameters could represent a therapeutic target to improve cognition even in the context of a structurally abnormal brain.\n\nHIGHLIGHTSO_LIEnvironmental enrichment (EE) in rats with cortical malformations improves cognition.\nC_LIO_LIEE resolves impaired rate and timing coding of hippocampal pyramidal neurons.\nC_LIO_LITaken together, circuit-level dynamics directly affect quality of the cognitive map.\nC_LI\n\nRESEARCH IN CONTEXTInsults during neurodevelopment, particularly those that result in physical malformations in the brain, lead to cognitive impairment, psychiatric disorders and epilepsy. Environmental enrichment (EE) improves cognitive outcome in patients and animal models with brain malformations. Understanding how EE can improve cognition at the level of neural networks can lead to new treatment targets. Remarkably, using an approach that mathematically models neuron firing we show that firing is mistimed in animals with malformations and that EE improves this abnormality. Importantly, timing abnormalities predict abnormalities in cognition at the single neuron level, suggesting that restoring timing could improve learning and memory deficits.

neuroscience↗