Scientific Understanding of Consciousness
Cortical Interneurons that Specialize in Disinhibitory Control
Nature 503, 521–524 (28 November 2013)
Cortical interneurons that specialize in disinhibitory control
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
Hyun-Jae Pi, Balázs Hangya, Duda Kvitsiani, Joshua I. Sanders, Z. Josh Huang & Adam Kepecs
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary
In the mammalian cerebral cortex the diversity of interneuronal subtypes underlies a division of labour subserving distinct modes of inhibitory control. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation. Although several interneuron populations are known to target other interneurons to varying degrees, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single-cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.
Cortical inhibitory interneurons display great diversity in their physiology, connectivity and synaptic dynamics, but it has long been debated whether and to what extent function of an interneuron type follows from a unique combination of these properties. The possibility that different interneuron cell types perform distinct circuit operations holds great promise for unravelling the logic of cortical microcircuits. Nevertheless, little is known about the functional roles of different interneuron subtypes, especially in awake and behaving animals. Multiple populations of interneurons differentially target distinct subregions of pyramidal cells leading to different modes of inhibitory control. Disinhibition of principal neurons mediated by inhibition targeted onto other inhibitory neurons can provide an additional layer of control, generating a powerful computational mechanism for increasing the gain of principal neurons. Recent work identified a population of layer 1 interneurons that mediate disinhibitory control over cortical processing and thereby enable associative learning. Previous studies proposed that VIP-expressing interneurons are a candidate cell type specializing in disinhibition because they seem to mainly target other interneurons. Indeed, VIP expression demarcates a small population of all interneurons (~15%), distinct from the two major interneuron populations defined by parvalbumin (PV; also called PVALB) and somatostatin (SOM) expression. However, whether and how VIP interneurons mediate disinhibition in vivo and when they are recruited during behaviour has remained elusive.
We examined the function of VIP interneurons in two functionally different cortical regions: auditory cortex (ACx) and medial prefrontal cortex (mPFC). Channelrhodopsin-2 (ChR2), a light-activated cation channel, was targeted to VIP neurons using a VIP-IRES-Cre knock-in mouse line by either breeding with Ai32 (ChR2 reporter line) or using viral delivery. To explore the function of VIP interneurons in circuit operations, we acquired extracellular recordings in awake mice using miniature microdrives that house an optical fibre and six tetrodes for simultaneous light stimulation and recording.
VIP interneurons function within a highly interconnected network, therefore their role can be understood as pre-synaptic drivers of (‘impact’) and post-synaptic responders to (‘recruitment’) other neurons. In terms of impact, we found that VIP neurons mediate disinhibitory control. In terms of recruitment, we identified a behaviourally relevant condition, reinforcement feedback, that uniformly activates VIP neurons. The homogeneous behavioural recruitment of VIP interneurons indicates that the synchronous ChR2-mediated activation to probe their circuit function was physiologically plausible. VIP interneurons are ideally positioned to serve as a substrate for long-range inputs to increase the gain of local cortical processing. Studies have recently demonstrated a similar disinhibitory process, whereby foot-shock-induced cholinergic activation of layer 1 cortical neurons in ACx enabled auditory fear learning. Interestingly, most VIP interneurons are located in superficial layers, including layer 1. However, the extent to which these two disinhibitory circuits overlap remains to be determined, as only a fraction of layer 1 interneurons express VIP. VIP interneurons express ionotropic receptors for cholinergic (nAChR) and serotonergic (5HT3a) modulation, indicating that they are also subject to rapid neuromodulation. These neuromodulatory systems or other long-range pathways probably convey information about reinforcement events to VIP neurons. By rapidly relaying this signal primarily to tone-selective neurons locally, VIP interneurons might contribute to cortical learning mechanisms. On the basis of these observations we propose that disinhibitory control by VIP interneurons provides a powerful circuit mechanism that enables long-range cortical signals or subcortical neuromodulation to efficiently modulate specific pyramidal neuron ensembles.
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