A Cortical Circuit for Gain Control by Behavioral State

“Attention, for example, has long been known to alter the cortical response to sensory stimuli (Fontanini and Katz, 2008; Maunsell and Cook, 2002; Posner and Petersen, 1990).”

“By crossing Ai14 (Cre-dependent TdTomato reporter) mice with vasoactive intestinal peptide (VIP)-Cre mice (Madisen et al., 2010; Taniguchi et al., 2011), we labeled VIP-positive GABAergic neurons genetically.”

“We first examined the responses of three major inhibitory neuron classes using adeno-associated viral (AAV) transfection of floxed GCaMP6s into the specific Cre-expressing mice (Chen et al., 2013).”

“However, electrophysiology alone does not allow one to distinguish among the large variety of GABAergic neurons with distinct physiological functions (Huang et al., 2007; Markram et al., 2004).”

“While an appropriate level of inhibition is known to be important for cortical plasticity, almost all previous work on experience-dependent plasticity has focused on the role of PV neurons (Hensch, 2005).”

“VIP neurons are present in both upper and deep layers, as shown previously (Taniguchi et al., 2011).”

“Furthermore, activating SST neurons also suppresses the visual response without changing OSI (Lee et al., 2012).”

“One interesting feature of VIP neurons is that they express serotonin receptor 5HT3a receptor (Lee et al., 2010; Rudy et al., 2011).”

“It has been reported that VIP neurons in V1 strongly inhibit SSTpositive inhibitory neurons (Pfeffer et al., 2013), whose activation results in suppression of the visual response of excitatory neurons (Adesnik et al., 2012).”

“Rabies-virus-based retrograde tracing (Wickersham et al., 2007) showed that the upper layer VIP neurons in V1 receive direct input from the nucleus of the diagonal band of Broca (NDB), a cholinergic center in basal forebrain.”

“Sensory responses have long been known to be modulated by behavioral state, but the neural circuit responsible for this modulation has remained obscure (Maunsell and Cook, 2002; Niell and Stryker, 2010; Reynolds and Chelazzi, 2004; Wurtz and Mohler, 1976).”

“It has recently been shown that VIP neurons also inhibit SST neurons in prefrontal and auditory cortices and that activating VIP neurons increases auditory responses (Pi et al., 2013).”

“Recent advances in mouse genetics and in vivo imaging technology now allow one to characterize the responses of different types of inhibitory neurons in the mouse V1 in awake animals that are free to run (Dombeck et al., 2010; Harvey et al., 2012; Taniguchi et al., 2011).”

“…Stony Brook University, Stony Brook, NY 11790, USA 4Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, CA 94158, USA *Correspondence: yufu@phy.ucsf.edu (Y.F.), stryker@phy.ucsf.edu (M.P.S.) http://dx.doi.org/10.1016/j.cell.2014.01.050”

“Using an apparatus that allows the mouse to run freely on a styrofoam ball floating on air while its head is fixed in space (Dombeck et al., 2010), we recorded the trackball movement and calcium signals simultaneously using two-photon imaging of neurons loaded with Oregon Green BAPTA (OGB-1), allowing us to analyze th…”

“No fast nAChR component like that shown in layer I inhibitory neurons (Letzkus et al., 2011) was evident; our findings showed instead a response with slow kinetics resembling what has been found in ChATpositive bipolar neurons (Arroyo et al., 2012).”

“…while SST neurons are inhibited during locomotion are in good agreement with the current consensus that VIP neuronsmainly innervate SST neurons (Lee et al., 2013; Pfeffer et al., 2013; Pi et al., 2013), although different effects on SST neurons have also been reported (Polack et al., 2013).”

“It has been reported that VIP neurons in V1 strongly inhibit SSTpositive inhibitory neurons (Pfeffer et al., 2013), whose activation results in suppression of the visual response of excitatory neurons (Adesnik et al., 2012).”

“A previous study also reported that some neurons are activated during running in darkness (Keller et al., 2012).”

“In particular, some putative inhibitory neurons were modulated differently from the more typical broad-spiking excitatory neurons (Chen et al., 2008; Mitchell et al., 2007; Niell and Stryker, 2010).”

“…while SST neurons are inhibited during locomotion are in good agreement with the current consensus that VIP neuronsmainly innervate SST neurons (Lee et al., 2013; Pfeffer et al., 2013; Pi et al., 2013), although different effects on SST neurons have also been reported (Polack et al., 2013).”

“One interesting feature of VIP neurons is that they express serotonin receptor 5HT3a receptor (Lee et al., 2010; Rudy et al., 2011).”

“Furthermore, activating SST neurons also suppresses the visual response without changing OSI (Lee et al., 2012).”

“Cholinergic input has been shown to modulate several aspects of visual response, such as the shift of local-field-potential spectrum and response magnitude (Metherate et al., 1992; Rodriguez et al., 2004; Sato et al., 1987a; Sato et al., 1987b), similar to what we have observed for locomotion (Niell and Stryker, 2010).”

“, 2002; Hill and Tononi, 2005), and one salient feature of awake cortical responses is powerful inhibition (Haider et al., 2013).”

“Changes in the balance between intrinsic excitatory and inhibitory conductances have long been linked to the change of brain state (Bazhenov et al., 2002; Hill and Tononi, 2005), and one salient feature of awake cortical responses is powerful inhibition (Haider et al.”

“Sensory responses have long been known to be modulated by behavioral state, but the neural circuit responsible for this modulation has remained obscure (Maunsell and Cook, 2002; Niell and Stryker, 2010; Reynolds and Chelazzi, 2004; Wurtz and Mohler, 1976).”

“In barrel cortex the SST neurons become hyperpolarized and fire fewer action potentials during active or passive whisker stimulation, in contrast to neighboring neurons that are excited by stimulation (Gentet et al., 2012).”

“Changes in the balance between intrinsic excitatory and inhibitory conductances have long been linked to the change of brain state (Bazhenov et al., 2002; Hill and Tononi, 2005), and one salient feature of awake cortical responses is powerful inhibition (Haider et al.”

“…Stony Brook University, Stony Brook, NY 11790, USA 4Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, CA 94158, USA *Correspondence: yufu@phy.ucsf.edu (Y.F.), stryker@phy.ucsf.edu (M.P.S.) http://dx.doi.org/10.1016/j.cell.2014.01.050”

“Inhibitory neurons may alter dendritic integration of sensory signals (Huber et al., 2012; Petreanu et al., 2012; Xu et al., 2012), and different inhibitory neurons have been hypothesized to play critical roles in behavioral state-dependent modulation of sensory processing (Buia and Tiesinga, 2008).”

“However, electrophysiology alone does not allow one to distinguish among the large variety of GABAergic neurons with distinct physiological functions (Huang et al., 2007; Markram et al., 2004).”

“In particular, some putative inhibitory neurons were modulated differently from the more typical broad-spiking excitatory neurons (Chen et al., 2008; Mitchell et al., 2007; Niell and Stryker, 2010).”

“It has also been shown that PV neurons do not respond to ACh (Kawaguchi, 1997) and are not directly activated by stimulating basal forebrain cholinergic neurons (Alitto and Dan, 2012; Arroyo et al.”

“Furthermore, besides increasing visual responses, locomotion has been shown to relieve surround suppression (Ayaz et al., 2013).”

“Cholinergic input has been shown to modulate several aspects of visual response, such as the shift of local-field-potential spectrum and response magnitude (Metherate et al., 1992; Rodriguez et al., 2004; Sato et al., 1987a; Sato et al., 1987b), similar to what we have observed for locomotion (Niell and Stryker, 2010).”

“Sensory-motor integration in rodents has been studied extensively in primary somatosensory barrel cortex, in which whisker movement and sensory information are sent to different segments of the same pyramidal neuron (Crochet et al., 2011; Petreanu et al., 2012; Xu et al., 2012).”

“Cholinergic input has been shown to modulate several aspects of visual response, such as the shift of local-field-potential spectrum and response magnitude (Metherate et al., 1992; Rodriguez et al., 2004; Sato et al., 1987a; Sato et al., 1987b), similar to what we have observed for locomotion (Niell and Stryker, 2010).”

“Acetylcholine has been demonstrated to play important roles in cortical activation and attentional modulation in many systems (Hasselmo and Giocomo, 2006; Weinberger, 2007).”

“Acetylcholine has been demonstrated to play important roles in cortical activation and attentional modulation in many systems (Hasselmo and Giocomo, 2006; Weinberger, 2007).”

“Attention, for example, has long been known to alter the cortical response to sensory stimuli (Fontanini and Katz, 2008; Maunsell and Cook, 2002; Posner and Petersen, 1990).”

“The midbrain locomotor center including the pedunculopontine tegmental nucleus (PPTg) projects to multiple subcortical and cortical areas, as well as to basal forebrain (Garcia-Rill, 1991; Newman et al., 2012).”

“Attention, for example, has long been known to alter the cortical response to sensory stimuli (Fontanini and Katz, 2008; Maunsell and Cook, 2002; Posner and Petersen, 1990).”

“Some VIP neurons reside in layer I or layer I/II border, and unidentified layer I interneurons have been reported to be activated by basal forebrain stimulation through nAChRs (Alitto and Dan, 2012; Letzkus et al., 2011).”

“No fast nAChR component like that shown in layer I inhibitory neurons (Letzkus et al., 2011) was evident; our findings showed instead a response with slow kinetics resembling what has been found in ChATpositive bipolar neurons (Arroyo et al., 2012).”

“Cholinergic input has been shown to modulate several aspects of visual response, such as the shift of local-field-potential spectrum and response magnitude (Metherate et al., 1992; Rodriguez et al., 2004; Sato et al., 1987a; Sato et al., 1987b), similar to what we have observed for locomotion (Niell and Stryker, 2010).”

“Inhibitory neurons may alter dendritic integration of sensory signals (Huber et al., 2012; Petreanu et al., 2012; Xu et al., 2012), and different inhibitory neurons have been hypothesized to play critical roles in behavioral state-dependent modulation of sensory processing (Buia and Tiesinga, 2008).”

“For example, the neurons in NDB and nearby nuclei have been found to respond not only to locomotion but also to other stimuli such as females (inmalemice) andwater (Mink et al., 1983).”

“VIP interneurons become highly active in relation to locomotion, whisking, or reinforcement signals (Fu et al., 2014; Lee et al., 2013; Pi et al., 2013).”

“This work corroborates studies showing that exercise shifts cortical circuits into excitatory states through GABAergic interneuron-mediated disinhibition of pyramidal neurons [234].”

“High-frequency oscillations in the gamma range were also enhanced during activity compared to quiet wakefulness (Figure S1B), consistent with previous reports (Niell and Stryker, 2010).”

“, 2015) is thought to be the consequence of neuromodulatory inputs (Fu et al., 2014; Polack et al., 2013), which exert context dependent influence on responses in visual cortex (Pakan et al.”

“One possible circuit involved in arousal-associated changes in cortical responsiveness is the cholinergic activation of inhibitory interneurons in layer 1, whose activity inhibits the activity of other classes of interneurons in layers 2/3 (Fu et al., 2014; Lee et al., 2013; Pi et al., 2013).”

“…peptide (VIP, 5HT3aR expressing) interneurons (Férézou et al., 2002), which inhibit both SST and PV interneurons seem to serve an important disinhibitory function in cortical circuits (Pi et al., 2013), that may help modulate the gain of pyramidal neuron responses (Fu et al., 2014).”

“…or tTA-expressing mouse lines (Haubensak et al., 2010; Wall et al., 2010; Weible et al., 2010; Miyamichi et al., 2011; Watabe-Uchida et al., 2012; Wall et al., 2013; Fu et al., 2014; Kohara et al., 2014; Ogawa et al., 2014; Pollak Dorocic et al., 2014; Sun et al., 2014; Weissbourd et al., 2014).”

“A promising and well-controlled starting point for this investigation would be appetitive Pavlovian conditioning, since both the cholinergic basal forebrain (Richardson and DeLong, 1991) and neocortical VIP interneurons (Pi et al., 2013) can be activated by reward.”

“Pvalb interneurons strongly inhibit nearby pyramidal cells and other Pvalb cells, Sst interneurons broadly inhibit nearby cells but avoid other Sst cells, and Vip cells selectively inhibit Sst cells and receive feedback excitation, forming a disinhibitory circuit (57, 58).”

“These three interneuron subtypes are thought to make up a canonical cortical circuit 7,31,36 .”

“Pulsed two-photon laser ablation of EGFP cells yields a higher degree of localized injury than continuous lasers, and has been successfully used to ablate organelles in single cells (29), as well as to sever individual dendrites of sensory neurons (30), and to functionally inactivate individual interneurons (31).”

“…intrinsic spiking properties (Hu et al., 2011; Lazarus and Huang, 2011; Miao et al., 2016), synaptic connectivity (Markram et al., 2004; Pfeffer et al., 2013; Karnani et al., 2016), and visual functions (Ma et al., 2010; Lee et al., 2012; Wilson et al., 2012; Cottam et al., 2013; Fu et al., 2014).”

“This activity dependence appears to be largely driven by the activation of nicotinic receptors (Fu et al. 2014).”

“Importantly, the changes that these neurochemicals impose on target cells are typically relatively slow (i.e., on the order of seconds), and thus provide a modulatory influence [32] over the signals that are conveyed by faster, ionotropic neurotransmitters, such as glutamate, γ-amino butyric acid (GABA), and the nicot…”

“We suggest that neuromodulatory inputs triggered by locomotion would not only activate VIP neurons through nicotinic acetylcholine receptors as previously shown (Alitto and Dan, 2012; Arroyo et al., 2014; Fu et al., 2014), but would also directly activate PV, SST, and excitatory neurons.”

“Furthermore, Fu et al. (2014) recently provided evidence supporting a general cortical microcircuit whereby cholinergic input to VIP interneurons communicates locomotor-related information.”

“…have begun to elucidate the cellular mechanisms underlying gain control in mouse visual cortex (Polack et al., 2013), including the roles of different classes of interneurons in gain modulation and sensory discrimination (Otte et al., 2010; Atallah et al., 2011; Fu et al., 2014; Lee et al., 2012).”

“VIP+ interneurons express nicotinic acetylcholine receptors (Fu et al., 2014), receive input from noradrenergic axons (Paspalas and Papadopoulos, 1999) and are members of a larger class of interneurons that express the ionotropic receptor subtype 5HT3A (Lee et al.”

“Cholinergic and noradrenergic neuromodulatory activity can rapidly mediate behaviorally-relevant gain increases in visual cortex; (Fu et al., 2014; Polack et al., 2013).”

“…the recently described function of VIP neurons as integrators of long-distance inputs into local cortical circuitry is dependent on both populations orwhether theymight contribute to different, but as yet unexplored functions (Lee et al. 2013; Pi et al. 2013; Fu et al. 2014; Zhang et al. 2014).”

“Nonfast spiking GABAergic neocortical neurons expressing vasoactive intestinal peptide increase their activity during whisking (Gentet et al., 2010; Lee et al., 2013), in part driven by nicotinic receptor activation (Fu et al., 2014).”

“Therefore, although VM does not appear to be a strong driver of PFC, it may regulate E/I balance, which plays a key functional role in the cortex (Fu et al., 2014; Letzkus et al., 2015), including within PFC (Kamigaki and Dan, 2017; Pi et al.”

“…interneurons target other GABAergic interneurons, disinhibiting excitatory pyramidal cells to increase excitatory gain based on behavioral context (Fu et al., 2014; Pfeffer et al., 2013; Zhang et al., 2014) or reinforcement signals (Hangya et al., 2014; Kepecs and Fishell, 2014; Pi et al., 2013).”

“Modulation of VIP neurons, as occurs in different behavioral states (Pi et al., 2013; Fu et al., 2014; Karnani et al., 2016a), is also a plausible candidate for the habituation signal.”

“Both cholinergic and noradrenergic inputs have been implicated in brain state dependent gain modulation (Polack et al., 2013; Pinto et al., 2013; Fu et al., 2014; Lee et al., 2014).”

“, 2013), indicating a locomotion-related state change that likely underlies the increased gain of visual responses (Fu et al., 2014; Polack et al., 2013).”

“ACh release from basal forebrain neurons excites layer 1 and VIP+ interneurons, which in turn inhibit local interneurons that target principle neurons of the cortex (Letzkus et al., 2011; Pinto et al., 2013; Fu et al., 2014).”

“…et al., 2003, Reyes et al., 1998, Silberberg and Markram, 2007, Kapfer et al., 2007), the local excitatory connections driving VIPs have remained poorly studied as recent studies suggest that VIPs specialize in receiving long-range excitation (Fu et al., 2014, Lee et al., 2013, Zhang et al., 2014).”

“…expressed a variant of channelrhodopsin, ChETA, in VIP neurons of binocular V1 by infecting VIP-Cre mice with AAV-DIO-ChETA-YFP (Figure 3A); we had previously shown this treatment to enhance visual responses of excitatory cells in stationary mice upon stimulation with blue light (Fu et al., 2014).”

“…target other interneurons (Lee et al. 2013, Pfeffer et al. 2013, Pi et al. 2013), mainly SST and a smaller fraction of PV interneurons, thereby providing disinhibitory control to principal neurons (Lee et al. 2013, Pi et al. 2013) and increasing response gain (Fu et al. 2014, Pi et al. 2013).”

“The lack of touchdriven activity in VIP neurons argues that whisking drives these neurons by cholinergic input acting on nicotinic receptors (Fu et al., 2014) or long-range excitatory input from the Yu et al.”

“These include a shift toward excitation in local cortical circuits (Fu et al., 2014), a generalized increase in surface electroencephalographic (EEG) power (Crabbe and Dishman, 2004), and a marked increase in whole-brain nonoxidative carbohydrate (CHO) consumption (Rasmussen et al., 2011).”

“Activation of VIP interneurons in the superficial layers is thought to result in disinhibition of PFC, as seen in other circuits (Letzkus et al., 2011; Lee et al., 2013; Pi et al., 2013; Fu et al., 2014).”

“, and Stryker, 800 M.P. (2014). A cortical circuit for gain control by behavioral state. Cell 156, 1139-1152. 801 Ganguly, K., and Carmena, J.M. (2009). Emergence of a stable cortical map for neuroprosthetic control. 802 PLoS biology 7, e1000153. 803 Greenberg, D.S., Wallace, D.J., Voit, K.-M., Wuertenberger, S., Czub…”

“…sensory traces is accomplished through the interaction of long-range neuromodulatory inputs with local excitatory-inhibitory microcircuits (Fu et al., 2014; Kuchibhotla et al., 2017; Letzkus et al., 2011; Marlin et al., 2015; Pi et al., 2013; Pinto et al., 2013; Schneider et al., 2014;…”

“Recent in vivo studies have implicated these cells in cortical disinhibition via the inhibition of SST-positive (SST ) neurons in several different cortical areas (Lee et al., 2013; Pi et al., 2013; Fu et al., 2014; Stryker, 2014; Zhang et al., 2014).”

“…(Hasselmo and Sarter, 2011), likely by desynchronizing neuronal networks to enhance the signal-to-noise ratio for salient informa- Ce This is an open access article und tion (Chen et al., 2015; Everitt and Robbins, 1997; Fu et al., 2014; Harris and Thiele, 2011; Hasselmo, 2006; Pinto et al., 2013).”