Scaling of Optogenetically Evoked Signaling in a Higher-Order Corticocortical Pathway in the Anesthetized Mouse

Abstract

Quantitative analysis of corticocortical signaling is needed to understand and model information processing in cerebral networks. However, higher-order pathways, hodologically remote from sensory input, are not amenable to spatiotemporally precise activation by sensory stimuli. Here, we combined parametric channelrhodopsin-2 (ChR2) photostimulation with multi-unit electrophysiology to study corticocortical driving in a parietofrontal pathway from retrosplenial cortex (RSC) to posterior secondary motor cortex (M2) in mice in vivo. Ketamine anesthesia was used both to eliminate complex activity associated with the awake state and to enable stable recordings of responses over a wide range of stimulus parameters. Photostimulation of ChR2-expressing neurons in RSC, the upstream area, produced local activity that decayed quickly. This activity in turn drove downstream activity in M2 that arrived rapidly (5–10 ms latencies), and scaled in amplitude across a wide range of stimulus parameters as an approximately constant fraction (~0.1) of the upstream activity. A model-based analysis could explain the corticocortically driven activity with exponentially decaying kernels (~20 ms time constant) and small delay. Reverse (antidromic) driving was similarly robust. The results show that corticocortical signaling in this pathway drives downstream activity rapidly and scalably, in a mostly linear manner. These properties, identified in anesthetized mice and represented in a simple model, suggest a robust basis for supporting complex non-linear dynamic activity in corticocortical circuits in the awake state.

Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons

“…The in vivo methods were recently described in detail 59 . Briefly, mice first underwent injection of AAV carrying ChR2 into either CA1 or AV, using the same coordinates and methods as described above for ex vivo experiments.…”

“…A digital high-pass filter (800 Hz cutoff, second-order Butterworth) was used to shrink the photovoltaic artifact to the first 3ms post-stimulus window. We analyzed multi- rather than single-unit activity; single units could not be reliably isolated in within the barrages of activity evoked by optogenetic stimulation 59 . For this, a threshold detector was applied with threshold set to the 4 times the standard deviation to detect spike-like events.…”

“…To mask the photovoltaic effect, spike counts of the 3 ms window from stimulus onset and offset were then replaced by null values (not-a-number, NaN, in Matlab). These data from each shank were then combined and used to construct peristimulus time histograms, averaged across trials 59 . After each recording, mice were immediately sacrificed for post-hoc analysis of recording position and injection site.…”

Identification of a novel perifornical-hypothalamic-area-projecting serotonergic system that inhibits innate panic and conditioned fear responses

“…Here it is likely that serotonin indirectly induces the GABA A -mediated inhibition of PFA-OX neurons via activation of GABAergic interneurons rather than direct release of GABA from the serotonergic terminals as very few (0.1-0.7%) of PFA-projecting serotonergic neurons in the DR and MR co-express GAD [69][70][71]. It remains unclear if the effects observed here by photostimulation are a direct result of only local 5-HT release [72][73][74][75][76] or if the optical stimulation also resulted in the release of 5-HT from collaterals via antidromic stimulation [77][78][79][80]. In our final experiments, we investigated the effect of the selective lesioning of lwDR/MR serotonergic projections on the PFA on panic and anxiety behaviors.…”

Bidirectional fear modulation by discrete anterior insular circuits in male mice

“…Our results are consistent with previous studies reporting that amygdala activation promotes fear responses (37), while thalamus activation, especially in the burst firing mode of the MD, reduces fear responses (38, 39). Although terminal optogenetic stimulation could produce antidromic activation (40), it only activates a subset of aIC neurons projecting to the areas. Our, therefore, study demonstrates for the first time that controlling distinct aIC outputs bidirectionally regulate fear behaviors.…”