Intersectional monosynaptic tracing for dissecting subtype-specific organization of GABAergic interneuron inputs

Abstract

Functionally and anatomically distinct cortical substructures such as areas or layers contain different principal neuron (PN) subtypes that generate output signals representing particular information. Various types of cortical inhibitory interneurons (INs) differentially but coordinately regulate PN activity. Despite a potential determinant for functional specialization of PN subtypes, the spatial organization of IN subtypes that innervate defined PN subtypes remains unknown. Here we develop a genetic strategy combining a recombinase-based intersectional labeling method and rabies viral monosynaptic tracing, which enables subtype-specific visualization of cortical IN ensembles sending inputs to defined PN subtypes. Our approach reveals not only cardinal but also underrepresented connections between broad, non-overlapping IN subtypes and PNs. Furthermore, we demonstrate that distinct PN subtypes defined by areal or laminar positions display different organization of input IN subtypes. Our genetic strategy will facilitate understanding of the wiring and developmental principles of cortical inhibitory circuits at unparalleled levels.

Ablation of striatal somatostatin interneurons affects MSN morphology and electrophysiological properties, and increases cocaine‐induced hyperlocomotion in mice

“…In the cortex, SSTi are the regulators of principal cell activity offering inhibitory mechanisms through GABAergic innervation that locally regulate dendritic computation (Chiu et al, 2013;Yetman et al, 2019). A reduction of SSTi number in the hippocampus and a consequent loss of inhibition drive to the excitatory input of the granule cells were found in the pilocarpine mice model of epilepsy (Hofmann, Balgooyen, Mattis, Deisseroth, & Buckmaster, 2016).…”

Opposing forms of adaptation in mouse visual cortex are controlled by distinct inhibitory microcircuits and gated by locomotion

“…6A-C. These begin with current understanding of the most basic circuit elements in V1 (Pfeffer et al, 2013;Pi et al, 2013;Tremblay et al, 2016;Yetman et al, 2019) on which we have superimposed the network dynamics observed in normal conditions (Figs. 1 and 2) and during a variety of optogenetic manipulations .…”

“…We began by investigating the role of PV interneurons which are the most numerous inhibitory subtype and have been shown to modulate the gain of visual responses in PCs (Celio, 1986;Atallah et al, 2012). PV interneurons are also relatively isolated within inhibitory networks of the cortex, making strong and direct connections with PCs but not transmitting significantly to SST or VIP interneurons (Yetman et al, 2019), making it easier to interpret their role in adaptation.…”

“…This is very likely to occur through PV cells ( Fig. 6C) given that these provide strong inhibitory inputs to all PCs (Pfeffer et al, 2013;Yetman et al, 2019) and an SST->PV disinhibition pathway has been shown to regulate visual responses in some PCs in V1 (Cottam et al, 2013;Pfeffer et al, 2013;Rikhye et al, 2017). SST interneurons can therefore drive sensitization in at least two distinct groups of PCs, one associated with a decrease in initial gain and the second with an increase (Fig.…”

“…There are many types of interneuron but the use of Cre-driver mouse lines has provided a way of separating the large majority of these into three broad groups, expressing one of Parvalbumin (PV), Somatostatin (SST) or Vasoactive Intestinal Polypeptide (VIP) (Tremblay et al, 2016). The connections between these and pyramidal cells (PCs) have been studied intensively (Pfeffer et al, 2013;Pi et al, 2013;Yetman et al, 2019) and have revealed some of the mechanism by which sensitivity in V1 is modulated in response to changes in internal state, in particular the dramatic increase in sensitivity synchronized to locomotor behaviour. Cholinergic inputs from the basal forebrain activated during running excite VIP interneurons which results in excitation of PCs through a VIP->SST disinhibition pathway (Fu et al, 2014;Niell and Stryker, 2010;Pakan et al, 2016;Dipoppa et al, 2018).…”