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

Abstract

Dorsal hippocampus, retrosplenial cortex (RSC), and anterior thalamic nuclei (ATN) 19interact to mediate diverse cognitive functions, but the cellular basis for these interactions 20 is unclear. We hypothesized a long-range circuit converging in layer 1 (L1) of RSC, based 21 on the pathway anatomy of GABAergic CA1 retrosplenial-projecting (CA1-RP) neurons 22 and thalamo-restrosplenial projections from ATN. We find that CA1→RSC projections 23 stem from GABAergic neurons with a distinct morphology, electrophysiology, and 24 molecular profile, likely corresponding to recently described Ntng1-expressing 25 hippocampal interneurons. CA1-RP neurons monosynaptically inhibit L5 pyramidal 26 neurons, principal outputs of RSC, via potent GABAergic synapses onto apical tuft 27 dendrites in L1. These inhibitory inputs align precisely with L1-targeting thalamocortical 28 excitatory inputs from ATN, particularly the anteroventral nucleus, forming a convergent 29 circuit whereby CA1 inhibition can intercept ATN excitation to co-regulate RSC activity. 30 Excitatory axons from subiculum, in contrast, innervate proximal dendrites in deeper 31 layers. Short-term synaptic plasticity differs at each connection. Chemogenetically 32 abrogating inhibitory CA1→RSC or excitatory ATN→RSC connections oppositely affects 33 the encoding of contextual fear memory. Collectively, our findings identify multiple cellular 34 mechanisms underlying hippocampo-thalamo-retrosplenial interactions, establishing CA1 35 RSC-projecting neurons as a distinct class with long-range axons that target apical tuft 36 dendrites, and delineating an unusual cortical circuit in the RSC specialized for integrating 37 long-range inhibition and thalamocortical excitation. 38 39 the neocortically projecting GABAergic neurons mentioned above, however, the cellular 55 properties of the presynaptic neurons are obscure, and the targets of their axons in the RSC are 56 unknown. 57This GABAergic CA1→RSC projection lies within a larger network thought to support 58 the encoding and storage of hippocampally derived information in the RSC (reviewed in 9-11 ). 59Understanding how the GABAergic neurons in CA1 are connected to postsynaptic RSC neurons 60 could thus yield mechanistic insight into the cellular basis for behaviors mediated by 61 hippocampo-retrosplenial communication in this system. 62 4 Hippocampo-retrosplenial communication also involves excitatory circuits, but unlike 63 GABAergic CA1→RSC projections these appear to be mostly indirect, through polysynaptic 64 chains of connections 12 . Two major routes carrying hippocampus-related information to the 65 RSC are a corticocortical pathway via subiculum, and a subcortical pathway traversing the 66 anterior thalamic nuclei (ATN). Subiculum→RSC projections arise from burst-firing vGlut1-or 67 vGlut2-expressing subicular pyramidal neurons, which directly excite RSC pyramidal neurons 13 . 68They also drive feedforward (disynaptic) inhibition 13 , a local-circuit inhibitory mechanism 69 previously implicated in mnemonic func...

A Gradient of Hippocampal Inputs to the Medial Mesocortex

“…While the amplitude of the responses tends to favor electrode contacts classified as "deep" in the previous experiment (n-way ANOVA, Amplitude, F(1,54)=22.14, p=0.0000, Bonferroni corrected for multiple comparisons, excitatory amplitude, p=0.0031, inhibitory amplitude p=0.0033), such contacts are located close to the cortical surface, something not seen when using the CaMKIIa-driven hChR2 ( Figure 5F). This is in agreement with previous anatomical findings (Miyashita and Rockland, 2007;Yamawaki et al, 2018), as well as our own, concerning the anatomical distribution of pan-neuronal terminals, in that there are indeed projections targeting the superficial RSC layers, but also conspicuous, vertically-oriented terminals ( Figure 3C, right panels), possibly providing GABAergic input to both the superficial and the deep sides of layers L3-4. Finally, we noted that the PTX-sensitive conductance we now describe has the same polarity as the CNQX and APV sensitive ones ( Figure 5D-E).…”

“…While we found GAD+ neurons widespread in all HIPP strata following injections on all regions, only following CTB-Alexa injections in RSC did we find neurons labeled with both CTB-Alexa and GAD ( Figure 3A), and only at the SR-SLM border, (50 double-labelled neurons out of 90 retrogradely labelled with CTB-Alexa, in 6 analyzed slices from 3 animals) indicating that ~50% of all HIPP neurons projecting to the RSC, but not to CG, are indeed LRIP located at the SR-SLM border. These numbers agree with the ones resulting from recent findings (Yamawaki et al, 2018). The identification of LRIP between HIPP, EC and RSC suggest that this type of projection constitutes a transregional network, gating the transfer of high-level sensory information possibly involved in the storage of complex contextual information.…”

Uniquely excitable neurons enable precise and persistent information transmission through the retrosplenial cortex

“…Similar impacts on both anterograde and retrograde memory are also seen in monkeys when the RSC is lesioned (Buckley and Mitchell, 2016). In rodents, RSC lesions impair performance on both spatial learning and fear conditioning tasks (Vann et al, 2003(Vann et al, , 2009; van Groen et al, 2004;Keene and Bucci, 2008;Katche et al, 2013;Todd et al, , 2017Sigwald et al, 2016;Yamawaki et al, 2019b). Recent imaging studies in mice confirm that RSC neurons can display evidence of longduration, persistent spatial memory engrams (Czajkowski et al, 2014;Milczarek et al, 2018;de Sousa et al, 2019;Hattori et al, 2019).…”

“…Of even more direct relevance is the persistent nature of the navigational information being received and processed by the superficial RSC. The subiculum represents one of these key functional inputs to RSC L2/3 cells (Wyss and van Groen, 1992;Yamawaki et al, 2019bYamawaki et al, , 2019a. Subicular neurons, particularly those in the postsubiculum, display a strong preference for particular orientations and are thus called head direction (HD) cells (Taube et al, 1990).…”

“…The RSC receives prominent spatial and memory-related inputs from the hippocampus, subicular complex, anterior thalamus, secondary motor cortex, and visual cortex, as well as the contralateral RSC Wyss, 1990, 2003;Wyss and van Groen, 1992;Miyashita and Rockland, 2007). Recent studies have started to document the functional nature of these inputs to the RSC (Yamawaki et al, 2016, 2019a, 2019bSempere-Ferràndez et al, 2018;Sempere-ferràndez et al, 2019). However, the precise properties of the RSC neuronal subtypes involved Sugar et al, 2011;Kurotani et al, 2013) is rarely studied and the local connectivity between RSC subtypes completely unknown.…”