Optogenetic fMRI in the mouse hippocampus: Hemodynamic response to brief glutamatergic stimuli

Abstract

The combination of optogenetics with functional magnetic resonance imaging is a promising tool to study the causal relationship between specific neuronal populations and global brain activity. We employed this technique to study the brain response to recruitment of glutamatergic neurons in the mouse hippocampus. The light-sensitive protein channelrhodopsin-2 was expressed in a-CamKII-positive glutamatergic neurons in the left hippocampus (N ¼ 10). Functional magnetic resonance imaging was performed during local laser stimulation, with stimulus duration of 1 second. The hemodynamic response to these stimuli was analyzed on a whole-brain level. In a secondary analysis, we examined the impact of the stimulation locus on the dorso-ventral axis within the hippocampal formation. The hemodynamic response in the mouse hippocampus had an earlier peak and a shorter duration compared to those observed in humans. Photostimulation was associated with significantly increased blood oxygen level-dependent signal in group statistics: bilaterally in the hippocampus, frontal lobe and septum, ipsilaterally in the nucleus accumbens and contralaterally in the striatum. More dorsal position of the laser fiber was associated with a stronger activation in projection regions (insular cortex and striatum). The characterization of brain-region-specific hemodynamic response functions may enable more precise interpretation of future functional magnetic resonance imaging experiments.

Acute Disruption of the Dorsal Hippocampus Impairs the Encoding and Retrieval of Trace Fear Memories

“…This more complete memory impairment suggests that the abnormal activity patterns induced by ChR2 stimulation disrupted encoding in brain regions that can normally compensate for the loss of the dorsal hippocampus. Consistent with this idea, stimulation of dCA1 has been shown to produce widespread increases in brain activity (Takata et al, 2015; Lebhardt et al, 2016). In contrast to our results, some studies have found that increases in CA1 activity during encoding enhance trace fear memory acquisition (Kitamura et al, 2014; Sellami et al, 2017).…”

Hierarchical cross-scale analysis identifies parallel ventral striatal networks coding for dynamic and stabilized olfactory reward predictions

“…Upon preprocessing (see Methods section and Fig. S2A-C ), we computed a general linear model (GLM) on the BOLD time series of the 51 sessions, modeling CS and US timepoints as events, which were parametrically modulated as described below, and convolved with a previously determined mouse hemodynamic response function (Lebhardt et al, 2016). When parametrically modulating the CS regressor with the model-estimated RP value at CS, V ( CS ), we observed broad recruitment of brain regions ( Fig.…”

“…As mentioned, the HRF varies significantly between species, with faster kinetics in mice compared to humans (Chen et al, 2020, Lebhardt et al, 2016, Schlegel et al, 2015). We therefore used a mouse-specific HRF estimated by Lebhardt et al, 2016. In all models, CS and US timepoints were modelled as events (“stick functions”, duration 0 s).…”

“…However, Wavelet Despiking has not been systematically assessed in task-related fMRI, where the frequency spectrum may be more heterogeneous than in resting-state fMRI. Additionally, in rodents, the hemodynamic response function (HRF) is faster than in primates (Chen et al, 2020, Lebhardt et al, 2016, Schlegel et al, 2015) and therefore has a weaker lowpass filtering effect, potentially allowing true neuronally-based BOLD signal to contain higher frequencies. In line with this, we found Wavelet Despiking to introduce implausible temporal “smearing” such that activations started slightly before the trial.…”

Connecting the dots between cell populations, whole-brain activity, and behavior

“…Lebhardt et al. 104 unilaterally applied optogenetic stimulation to the hippocampus of CaMKIIα-Cre mice and found that glutamatergic neuron activity in the hippocampus (dependent on where along the dorso-ventral axis) led to a significant positive BOLD response, bilaterally at the site of stimulation, frontal lobe, and septum; ipsilaterally in the nucleus accumbens (NAc); and contralaterally in the striatum. Opto-fMRI of the ventrolateral orbitofrontal cortex (VLO) showed that this area also exhibits a global influence on brain activity.…”