Regulation of locomotion by hippocampal theta oscillations revealed by optogenetic entrainment

Hippocampal theta oscillations (5-10 Hz, Jung and Kornmüller, 1938) occur during exploration and REM sleep (Buzsáki, 2002). The medial septum is an essential theta rhythm generator (Petsche et al., 1962) and forwards ascending inputs to the hippocampus (Bland and Oddie, 2001). Among the neuronal populations within the medial septum GABAergic neurons exhibits theta rhythmic burst firing (Hangya et al., 2009) and have been suggested to rhythmically disinhibit hippocampal pyramidal cells via innervation of hippocampal interneurons (Freund and Antal, 1988). During locomotion the frequency of theta oscillations is correlated with running speed (Vanderwolf, 1969). However, whether hippocampal theta oscillations regulate locomotor speed remained a long-standing question (Vanderwolf, 1969; Grastyan et al., 1959), as electrical stimulation of ascending hippocampal afferent regions inevitably involves unspecific activation of brain circuitry involved in locomotor control (Green and Arduini, 1954). Only since recently distinct brain pathways can be manipulated with high spatial and temporal precision using optogenetics (Yizhar et al., 2011b). In this study, we achieved entrainment of hippocampal theta oscillations by rhythmic optogenetic stimulation of medial septal GABAergic cell terminals in the hippocampus. When the frequency of theta oscillations was optogenetically controlled, it was no longer correlated with running speed. Hence, as indicated by earlier lesion and pharmacological studies (reviewed in Bland and Oddie, 2001), the association of theta frequency with running speed is mediated by ascending afferents. We next found that the entrainment of hippocampal theta oscillations, regardless of stimulation frequency within the theta range (6-12 Hz), mediated slower and more regular running speed. The optogenetic entrainment promoted a lower variability of theta amplitude. A correlation between theta amplitude variability and running speed was observed for optogenetically entrained as well as for spontaneous theta oscillations. Further analysis of the data (Bender et al., 2015) indicated that lower amplitude variability is associated with a more stable output of pyramidal cells across theta cycles. Moreover, we revealed that the behavioural effect disappeared when the main hippocampal subcortical output, to the lateral septum (LS, Risold and Swanson, 1996), was inhibited: pharmacoor optogenetic inhibition of this pathway prevented the decrease in speed or speed variability during entrainment of hippocampal theta oscillations. The LS is also innervated by the medial prefrontal cortex (mPFC, CarusCadavieco et al., 2017), which guides goal-directed behaviour (Miller and Cohen, 2001). Cognitive processes are linked to gamma oscillations (30-90 Hz, Cardin et al., 2009, Kim et al., 2016), which allow binding of sensory, e.g. visual, informations into complex representations (Singer and Gray, 1995). We found that optogenetic stimulation of the mPFC to LS pathway at gamma frequencies did not influence running speed, but improved performance in a spatial food-rewarded learning task. In conclusion, our findings suggest that hippocampal theta oscillations can regulate locomotor speed via the LS and gamma oscillations within the mPFC to LS pathway support spatial goal-directed behaviour.