Optogenetic “low‐theta” pacing of the septohippocampal circuit is sufficient for spatial goal finding and is influenced by behavioral state and cognitive demand

Abstract

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.

Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

“…The hippocampal response to MS stimulation in weanling rats was precise and robust. As with previous studies in adult rats from our laboratory [34,42] and others [46e49], optogenetic stimulation resulted in robust regulation of hippocampal oscillations with precise 1:1 entrainment of stimulation to hippocampal EEG at a wide range of frequencies. Stimulation at 5e12 Hz resulted in increases in power in the theta bandwidths, but also in the delta and beta bandwidths in both hippocampus and MS electrodes.…”

“…EEG Recordings: All EEG analyses were performed using Neu-roExplore 4 software (Nex Technologies, Madison, AL). Power spectrum density (PSD), coherences and EEG correlations were obtained for each rate at each optogenetic stimulation frequency using methods previously described in our laboratory [41,42]. The following oscillatory properties using local EEG were calculated for each animal: PSD: After a single taper with the Hamming windowing function the fast Fourier transform (FFT) of the EEG was calculated for from 0 to 50 or 0e100 Hz depending on the stimulating condition.…”

Medial septal GABAergic neurons reduce seizure duration upon optogenetic closed-loop stimulation

“… 79 Therefore, stimulation of one population of neurons may modulate the other, or both neurotransmitters may be released upon stimulation of either population, consequently resulting in non-specific effects. Indeed, while our experiments establish a proof-of-principle for the effectiveness of closed-loop optical stimulation of MSGNs, non-selective activation of medial septum projections may be sufficient to modulate hippocampal oscillations 67 , 80 and reduce seizure frequencies. 81 …”

“…A recent report suggests that pan-neuronal stimulation of medial septal neurons does not perturb active spatial memory. 67 Additionally, both medial septal electrical stimulation in a chronic TLE rat model 68 and optogenetic stimulation of parvalbumin MSGNs in an Alzheimer’s disease mouse model, 69 improve spatial memory deficits.…”

Effects of early life seizures on coordination of hippocampal–prefrontal networks: Influence of sex and dynamic brain states

“…The results of the ROC analysis in dynamic theta further suggest that the 8‐Hz theta frequency has an important role in facilitating neural transmission between CA1 and mPFC, and generating avoidance behavior. Future experiments could use optogenetic stimulation to explore the necessity of the 8‐Hz bandwidth in controls, as well as the functional role of low‐theta frequencies in females and ELS‐M rats that learn the active avoidance task 49 …”