Optogenetic "low-theta" pacing of the septohippocampal circuit is sufficient for spatial goal finding and is influenced by behavioral state and cognitive demand.

Hippocampal theta oscillations show prominent changes in frequency and amplitude depending on behavioral state or cognitive demands. How these dynamic changes in theta oscillations contribute to the spatial and temporal organization of hippocampal cells, and ultimately behavior, remain unclear. We used low-theta frequency optogenetic stimulation to pace coordination of cellular and network activity between the medial septum (MS) and hippocampus during baseline and MS stimulation while rats were at rest or performing a spatial accuracy task with a visible or hidden goal zone. Hippocampal receptivity to pan-neuronal septal stimulation at low-theta frequency was primarily determined by speed and secondarily by task demands. Competition between artificial and endogenous field potentials at theta frequency attenuated hippocampal phase preference relative to local theta, but the spike-timing activity of hippocampal pyramidal cells was effectively driven by artificial septal output, particularly during the hidden goal task. Notwithstanding temporal reorganization by artificial theta stimulation, place field properties were unchanged and alterations to spatial behavior were limited to goal zone approximation. Our results indicate that even a low-theta frequency timing signal in the septohippocampal circuit is sufficient for spatial goal finding behavior. The results also advance a mechanistic understanding of how endogenous or artificial somatodendritic timing signals relate to displacement computations during navigation and spatial memory.

Functional brain connectivity in a rodent seizure model of autistic-like behavior.

OBJECTIVE: There is increasing evidence that Autism Spectrum Disorder (ASD) is a disorder of functional connectivity with both human and rodent studies demonstrating alterations in connectivity. Here, we hypothesized that early-life seizures (ELS) in rats would interrupt normal brain connectivity and result in autistic-like behavior (ALB). METHODS: Following 50 seizures, adult rats were tested in the social interaction and social novelty tests and then underwent qualitative and quantitative intracranial electroencephalography (EEG) monitoring in the medial prefrontal cortex (PFC) and the hippocampal subfields, CA3 and CA1. RESULTS: Rats with ELS showed deficits in social interaction and novelty, and compared with control, rats had marked increases in coherence within the hippocampus (CA3-CA1) and between the hippocampus and PFC during the awake and sleep states indicating hyperconnectivity. In addition, sleep spindle density was significantly reduced in rats with ELS. There were no differences in voltage correlations and power spectral densities between the ELS and control rats in any bandwidths. CONCLUSION: Taken together, these findings indicate that ELS can result in ALB and alter functional connectivity as measured by coherence and sleep spindle density. These findings implicate altered connectivity as a robust neural signature for ALB following ELS.

Efficacy of nonselective optogenetic control of the medial septum over hippocampal oscillations: the influence of speed and implications for cognitive enhancement.

Optogenetics holds great promise for both the dissection of neural circuits and the evaluation of theories centered on the temporal organizing properties of oscillations that underpin cognition. To date, no studies have examined the efficacy of optogenetic stimulation for altering hippocampal oscillations in freely moving wild-type rats, or how these alterations would affect performance on behavioral tasks. Here, we used an AAV virus to express ChR2 in the medial septum (MS) of wild-type rats, and optically stimulated septal neurons at 6 Hz and 30 Hz. We measured the corresponding effects of these stimulations on the oscillations of the MS and hippocampal subfields CA1 and CA3 in three different contexts: (1) With minimal movement while the rats sat in a confined chamber; (2) Explored a novel open field; and (3) Learned and performed a T-maze behavioral task. While control yellow light stimulation did not affect oscillations, 6-Hz blue light septal stimulations altered hippocampal theta oscillations in a manner that depended on the animal's mobility and speed. While the 30 Hz blue light septal stimulations only altered theta frequency in CA1 while the rat had limited mobility, it robustly increased the amplitude of hippocampal signals at 30 Hz in both regions in all three recording contexts. We found that animals were more likely to make a correct choice during Day 1 of T-maze training during both MS stimulation protocols than during control stimulation, and that improved performance was independent of theta frequency alterations.