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

Abstract

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.

Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies

“…2d, e). We also addressed whether the efficiency of pacing is dependent on the running speed, and found that at 10 Hz, pacing by MSA stimulation was particularly effective at rest and low running speeds, consistent with previous reports that theta can be paced optogenetically in this state [30, 34] (Supplemental fig. 2f).…”

“…Similarly, rhythmic hippocampal oscillations can also be driven by electrical stimulation of the fornix while the MSA is inactivated [31, 32] or by nonselective optical stimulation of septal cells [33, 34]. Taken together, these recordings have therefore shown that MSA stimulation can elicit theta-like oscillations in brain states when the theta rhythm is not typically observed.…”

Reconciling the different faces of hippocampal theta: The role of theta oscillations in cognitive, emotional and innate behaviors

“…Locomotion-dependent activity of MS cells, interconnected with subcortical regions, including several hypothalamic nuclei, is thought to underlie matching of theta frequency to changing running speed (Bland et al, 2006). Optogenetic stimulation of MS cells at theta frequency (without specificity for cell type) in freely moving rats affected hippocampal theta oscillations in a speed-depended dependent manner, being stronger at slower speeds (Blumberg et al, 2016).…”

Medial septum differentially regulates dopamine neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways

“…It is well-established that the MS, via its projection to the hippocampus, plays a key role in learning and memory. For example, lesion of the septohippocampal pathway leads to deficits in spatial memory [16] and spatial working memory [18,43,44], whereas optogenetic activation of the MS improves Tmaze performance [45] and fear learning [46]. While the mechanism for these effects remain unclear, it is hypothesized that MS regulation of hippocampal theta may play a role [14,15].…”