Yamawaki, N. | bioRxiv Science

bioRxiv2018

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

Dorsal hippocampus, retrosplenial cortex (RSC), and anterior thalamic nuclei (ATN) interact to mediate diverse cognitive functions, but the cellular basis for these interactions is unclear. We hypothesized a long-range circuit converging in layer 1 (L1) of RSC, based on the pathway anatomy of GABAergic CA1 retrosplenial-projecting (CA1-RP) neurons and thalamo-restrosplenial projections from ATN. We find that CA1[->]RSC projections stem from GABAergic neurons with a distinct morphology, electrophysiology, and molecular profile, likely corresponding to recently described Ntng1-expressing hippocampal interneurons. CA1-RP neurons monosynaptically inhibit L5 pyramidal neurons, principal outputs of RSC, via potent GABAergic synapses onto apical tuft dendrites in L1. These inhibitory inputs align precisely with L1-targeting thalamocortical excitatory inputs from ATN, particularly the anteroventral nucleus, forming a convergent circuit whereby CA1 inhibition can intercept ATN excitation to co-regulate RSC activity. Excitatory axons from subiculum, in contrast, innervate proximal dendrites in deeper layers. Short-term synaptic plasticity differs at each connection. Chemogenetically abrogating inhibitory CA1[->]RSC or excitatory ATN[->]RSC connections oppositely affects the encoding of contextual fear memory. Collectively, our findings identify multiple cellular mechanisms underlying hippocampo-thalamo-retrosplenial interactions, establishing CA1 RSC-projecting neurons as a distinct class with long-range axons that target apical tuft dendrites, and delineating an unusual cortical circuit in the RSC specialized for integrating long-range inhibition and thalamocortical excitation.

neuroscience↗

bioRxiv2017

Corticocortical signaling drives activity in a downstream area rapidly and scalably

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 (~0.2) 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.\n\nSIGNIFICANCE STATEMENTThe signaling properties of corticocortical connections are not well understood, particularly for higher-order inter-areal pathways. Here, we developed a paradigm based on parametric optogenetic photostimulation, linear-array electrophysiology, and mathematical modeling to characterize signaling along corticortical connections linking retrosplenial cortex to posterior secondary motor cortex (M2) in anesthetized mice. The results indicate that corticocortically driven activity in the downstream area followed the optogenetically evoked upstream activity in a rapid and scalable manner, and could be described with a simple linear integrator model. These findings suggest that this pathway, when activated selectively in the unconscious state, supports intrinsically linear inter-areal communication.

neuroscience↗