Intrinsic and Extrinsic Neuromodulation of Olfactory Processing

Neuromodulation is a ubiquitous feature of neural systems, allowing flexible, context specific control over network dynamics. Neuromodulation was first described in invertebrate motor systems and early work established a basic dichotomy for neuromodulation as having either an intrinsic origin (i.e., neurons that participate in network coding) or an extrinsic origin (i.e., neurons from independent networks). In this conceptual dichotomy, intrinsic sources of neuromodulation provide a “memory” by adjusting network dynamics based upon previous and ongoing activation of the network itself, while extrinsic neuromodulators provide the context of ongoing activity of other neural networks. Although this dichotomy has been thoroughly considered in motor systems, it has received far less attention in sensory systems. In this review, we discuss intrinsic and extrinsic modulation in the context of olfactory processing in invertebrate and vertebrate model systems. We begin by discussing presynaptic modulation of olfactory sensory neurons by local interneurons (LNs) as a mechanism for gain control based on ongoing network activation. We then discuss the cell-class specific effects of serotonergic centrifugal neurons on olfactory processing. Finally, we briefly discuss the integration of intrinsic and extrinsic neuromodulation (metamodulation) as an effective mechanism for exerting global control over olfactory network dynamics. The heterogeneous nature of neuromodulation is a recurring theme throughout this review as the effects of both intrinsic and extrinsic modulation are generally non-uniform.


INTRODUCTION
Neuromodulation adjusts the biophysical and synaptic properties of neurons, allowing fine control over network dynamics (Kupfermann, 1979;Kaczmarek and Levitan, 1987;Katz, 1999). Foundational work from invertebrate motor systems (Harris-Warrick and Marder, 1991;Katz, 1995;Frost, 1995, 1996) identified two major categories of neuromodulation that modify network processing under different circumstances; intrinsic neuromodulation vs. extrinsic neuromodulation. Intrinsic neuromodulation is exerted by neurons that are within a neural network and participate in information processing undertaken by that network. The amount of intrinsic neuromodulation depends on past or ongoing network activity and provides a ''memory'' of the network state. Extrinsic neuromodulation is exerted by neurons that originate in independent networks and therefore provide information based on the activity of other neural networks. These can be centrifugal neurons innervating a given network or endocrine cells that release humoral factors. The amount of extrinsic neuromodulation therefore depends on the activity of other networks, rather than the network that is being modulated. Thus, extrinsic neuromodulation provides a context about the broader state of the animal.
The buccal ganglion of Aplysia californica, which coordinates motor output to control biting movements, illustrates the influence of both intrinsic and extrinsic modulation within a single network (Morgan et al., 2000). The cerebral interneuron ''CBI-2'' initiates and directly participates in biting motor programs, making it an intrinsic element of the feeding central pattern generator (CPG). With each motor program, CBI-2 improves bite articulation via several neuromodulators (Morgan et al., 2000;Weiss, 2005, 2007;Friedman and Weiss, 2010;Dacks et al., 2012b). Biting motor programs can also be modulated based on prior exposure to food (Kupfermann, 1974) via the serotonergic metacerebral cells (MCCs) which are external to the feeding CPG. The MCCs do not initiate biting motor programs, yet their activity decreases latency of motor program initiation (Kupfermann, 1979;Kupfermann and Weiss, 1982;Morgan et al., 2000) and lesioning the MCCs reduces the frequency of biting (Rosen et al., 1989). Finally, the MCCs (the extrinsic modulators) shorten feeding motor program latency by increasing CBI-2 (the intrinsic modulator) quantal content (Proekt and Weiss, 2003). This ''metamodulation'' demonstrates how extrinsic modulators can target intrinsic modulatory components to exert contextual control over network activity (Katz, 1999).
While this conceptual dichotomy (intrinsic vs. extrinsic neuromodulation) has been extensively explored in motor systems, it has received less attention in sensory systems. Here, we take advantage of the depth of work on neuromodulation of olfaction to discuss mechanisms of intrinsic and extrinsic modulation within the first processing stage of the olfactory systems of mammals and insects. The intent of this review is to discuss the concepts of intrinsic and extrinsic modulation to the olfactory system and is by no means exhaustive. As an exemplar of intrinsic modulation, we discuss GABAb-mediated presynaptic inhibition as a means of gain-control modulating the dynamic range of the olfactory system based on previous and ongoing network activity. For extrinsic modulation, we discuss serotonergic inputs from outside the olfactory system that target specific neuron classes via differential receptor expression. We then discuss how serotonergic modulation of GABAergic interneurons provides an elegant mechanism by which metamodulation can use pre-existing gain control mechanisms to efficiently adjust network dynamics. Finally, we discuss the heterogeneous nature of neuromodulation throughout this review, as populations of neurons, and even the arbors of a single neuron, display a surprising degree of molecular and synaptic heterogeneity.

ANATOMY OF THE OLFACTORY SYSTEM AND SOURCES OF NEUROMODULATION
There are many parallels between the insect and vertebrate olfactory systems (Hildebrand and Shepherd, 1997;Ache and Young, 2005). Notably, for this review, both are subject to a broad suite of neuromodulators. In the insect antennal lobe (AL), odorants bind to chemosensory proteins expressed by input neurons called olfactory sensory neurons (OSNs; Figure 1A).
Similarly, in the vertebrate olfactory system odorants activate OSNs in the olfactory epithelium which project into glomeruli in the olfactory bulb (OB; Figure 1B). OSNs synapse onto two types of output neurons called mitral and tufted (M/T) cells, which send olfactory information in part to the piriform cortex, olfactory tubercle and other secondary targets. Much like insects, the OB relies on heterogeneous populations of LNs to refine M/T cell output. Subtypes of LNs in the glomerular layer (''juxtaglomerular neurons'') exhibit complex connectivity with the major OB cell types (Wachowiak and Shipley, 2006). Juxtaglomerular neurons can be subdivided into three classes. GABAergic periglomerular cells (PG) synapse onto M/T cells and have an unconventional inhibitory relationship with OSNs in which PG cells may influence OSNs via GABAergic spillover and not via a traditional inhibitory synapse (Pinching and Powell, 1971;Aroniadou-Anderjaska et al., 2000;Wachowiak et al., 2005). Glutamatergic external tufted cells (ET) synapse onto PG cells, M/T cells and superficial short axon cells (sSA). There is evidence that subsets of PG and ET cells may also release DA (Kosaka and Kosaka, 2016). Finally, GABAergic/DAergic sSA cells synapse onto OSNs, and ETs, and widely interconnect both neighboring and distant glomeruli in the glomerular layer (Aungst et al., 2003;Kiyokage et al., 2010;Liu et al., 2013). In the granule cell (GC) layer of the OB, GABAergic GCs provide feedback inhibition onto M/T cells (Shepherd et al., 2007;Burton, 2017). Furthermore, GABAergic deep short axon cells (dSA; Eyre et al., 2008;Burton et al., 2017) synapse onto themselves and reciprocally synapse upon GCs (Burton, 2017). PG and ET cells also appear to express a wide variety of neuropeptides, including NPY, VIP and CCK (Seroogy et al., 1985;Gall et al., 1986). The OB is also subject to extrinsic sources of modulation including 5-HT, norepinephrine (NE) and acetylcholine (ACh), that are FIGURE 1 | Intrinsic and extrinsic sources of neuromodulation in the insect and vertebrate olfactory system. (A) In the insect antennal lobe (AL), all three principal neuron types, olfactory sensory neurons (OSNs), local interneurons (LNs), and projection neurons (PNs) are subject to both intrinsic and extrinsic sources of modulation. GABA (magenta), dopamine (DA; yellow), and a suite of neuropeptides (green) released by LNs act as intrinsic modulators, while serotonin (5-HT; blue), DA, and octopamine (OCT; orange) act as extrinsic modulators to contextually alter olfactory processing. DA can be extrinsic or intrinsic depending on the species. (B) In the vertebrate olfactory bulb (OB), subtypes of LNs broadly serve as sources of intrinsic modulation. GABAergic periglomerular cells (PG), glutamatergic external tufted cells (ET; light green) and GABAergic/DAergic superficial short axon cells (sSA; magenta/yellow) synapse onto OSNs, mitral and tufted cells (M/Ts) and each other in the glomerular layer. GABAergic granule cells (GC) synapse onto M/Ts to alter OB output and GABAergic deep short axon cells (dSA) both reciprocally synapse onto themselves and GCs. Both the AL and OB are innervated by extrinsic sources of 5-HT, norephinephrine (NE; pink), and acetylcholine (ACh; dark purple). The "∼" symbol at the PG to OSN synapse indicates that this is a non-traditional synapse that depends upon GABA spillover. released from centrifugal neurons outside of the OB (McLean and Shipley, 1987;Cleland, 2002, 2016;Kiselycznyk et al., 2006;Matsutani and Yamamoto, 2008;Fletcher and Chen, 2010;Steinfeld et al., 2015).

INTRINSIC MODULATION AS A MEANS OF PRESYNAPTIC GAIN CONTROL
The olfactory system must efficiently encode odorant information over a wide concentration range to produce reliable representations of odor identity. Heterogeneous populations of LNs and juxtaglomerular neurons alter the input/output relationship between principal cell types to accomplish much of this computation. LNs can release a variety of transmitters including many neuromodulators that act over a range of timescales and in Drosophila, lateral input from inhibitory LNs scales with overall network activation (Olsen and Wilson, 2008). Thus, LNs intrinsically modulate odor coding within the context of current and previous network activation. Intrinsic modulation of olfactory processing can: (1) alter network output based on the strength of odor input; (2) mediate long-lasting temporal effects via metabotropic receptors; and (3) regulate the dynamic range of output neurons, allowing for reliable coding of odor identity across a range of stimulus intensities.
The information transferred from individual OSNs to PNs is highly reliable (Murphy et al., 2004) yet non-linear (Wilson et al., 2004;Bhandawat et al., 2007;Olsen and Wilson, 2008). At high stimulus intensities, output neuron activity can saturate such that further increases in OSN output do not result in a concomitant increase in output neuron activity. To avoid saturation, the olfactory system relies on presynaptic inhibition as a means of gain control. Gain control adjusts the signal strength between input and output neurons to filter out noise from spontaneous firing of OSNs (Wilson, 2013), avoid saturation (Martin et al., 2011) and adjust the dynamic range of output neurons (Olsen and Wilson, 2008;Root et al., 2008). It does this, broadly, by activating GABAb receptors on presynaptic terminals to reduce presynaptic calcium levels, resulting in reduced transmitter release from the presynaptic neuron (Figure 2A; Wang, 2012). While early studies on GABAergic inhibition in the insect AL focused on the role of ionotropic GABAa mediated lateral inhibition (Waldrop et al., 1987;Christensen et al., 1993Christensen et al., , 1998aLei et al., 2002), GABAa blockade in insects does not fully block a slower form of inhibition (MacLeod and Laurent, 1996; FIGURE 2 | Intrinsic modulation as a means of presynaptic gain control. (A) Presynaptic gain control alters the signal strength between OSNs and PNs to filter out noise from spontaneous firing of OSNs, avoid PN saturation and expand the dynamic range of PNs. It does this by reducing presynaptic calcium levels in OSNs via GABAb receptors, and reducing the likelihood of acetycholine release onto PNs. (B) GABAb blockade (red) increases presynaptic calcium influx and decreases the range of OSN input over which PN firing rate can change, ultimately resulting in PN saturation (based on results from Root et al., 2008;Olsen et al., 2010). (C) GABAergic lateral inhibition scales with network activation (as measured by OSN activity; Olsen and Wilson, 2008). Christensen et al., 1998b;Bazhenov et al., 2001;Wilson et al., 2004;Wilson and Laurent, 2005). A slower GABA component had also been suggested as GABAb receptor agonists reduce the responses of M/T cells responses to olfactory nerve stimulation (Nickell et al., 1994). Together this suggested that: (1) GABA may also act presynaptically; and (2) a slower, metabotropic mechanism is at play.
In Drosophila melanogaster, GABAb blockade on OSN terminals increases presynaptic calcium influx, broadens odor tuning of PNs and decreases the range of OSN input over which PN firing rate can change, ultimately resulting in PN saturation (Figure 2B; Olsen and Wilson, 2008;Root et al., 2008). In normal conditions, PN responses are normalized via increased lateral inhibition which scales with ORN activity (Figure 2C; Olsen et al., 2010). Overall, this suggests that interglomerular presynaptic inhibition adjusts the dynamic range of PNs to avoid saturation and refines the breadth of odor tuning across a wide range of stimulus intensities (Wang, 2012). It is important to note that GABA is not the sole modulator of gain control in this system, as the neuropeptides tachykinin (Ignell et al., 2009), and short neuropeptide F (Root et al., 2011;Ko et al., 2015) also mediate presynaptic inhibition.
However, it is still unclear whether presynaptic inhibition mediates gain control in the OB. A hallmark of gain control is that inhibition is stronger at higher stimulus intensities and weaker at lower stimulus intensities (Robinson and McAlpine, 2009;Saalmann and Kastner, 2009;Martin et al., 2011;Wang, 2012). To demonstrate that presynaptic inhibition adjusts the dynamic range of OB output, presynaptic inhibition must scale with odor concentration. One study found that both weak and strong odor-evoked inputs are subject to the same amount of GABAergic inhibition, and tonic inhibition does not scale with the strength of OSN activation (Pirez and Wachowiak, 2008). This suggests that presynaptic inhibition may alter OSN sensitivity, rather than adjust the dynamic range of M/T cells. Another study demonstrated that juxtaglomerular GABA/DAergic cells, likely sSA cells, exert concentration dependent gain control onto M/T cells (Banerjee et al., 2015). However, it is unclear whether this gain control has a presynaptic component, as this study focused on the synaptic interactions of ET, sSA and M/T cells. Finally, activation of GABA/DAergic sSA cells inhibit presynaptic OSNs, resulting in decreased spiking in M/T cells, and M/T attenuation is blocked by GABAb and D 2 receptor antagonists (Vaaga et al., 2017). However, this does not rule out a GABAb-dependent postsynaptic mechanism of gain control, as sSA activation could act via multiple synapses to control M/T output. Finally, it is still unclear which exact subpopulation(s) of neurons mediate presynaptic inhibition. Potential sources include GABA spillover from GABAergic PG neurons (Aroniadou-Anderjaska et al., 2000;Wachowiak et al., 2005), direct inhibition of OSNs via GABA from sSA (Vaaga et al., 2017), or altered glutamatergic ET cell activity to indirectly influence OB output (Pirez and Wachowiak, 2008;Banerjee et al., 2015).

Local Interneuron Heterogeneity
While presynaptic inhibition is ubiquitous, it is not exerted evenly across the olfactory system. In Drosophila, some glomeruli are more subject to inhibition than others simply due to differences in glomerulus-specific LN innervation (Wilson and Laurent, 2005;Chou et al., 2010) and OSN GABAb receptor expression (Root et al., 2008). This suggests that specific odors differ in the amount of ''shelter'' they need from ongoing activity in the olfactory system, and are therefore insulated from presynaptic gain control. Furthermore, LNs and juxtaglomerular neurons are heterogeneous in their morphology, physiology and transmitter content (Seki and Kanzaki, 2008;Carlsson et al., 2010;Chou et al., 2010;Seki et al., 2010;Reisenman et al., 2011;Nagayama et al., 2014). Consequently, this heterogeneity has made it challenging to determine the sub-populations of neurons involved and the mechanisms by which they mediate presynaptic gain control. For example, individual LNs in the moth Manduca sexta likely express up to five transmitters, and co-expression of neuropeptides is variable across the entire population (Lizbinski et al., 2017). Thus, few LNs expresses the same combination of transmitters, resulting a dynamic cocktail of neuromodulators that regulate the modulatory tone of the network. Overall this suggests that while LNs and juxtaglomerular neurons function as intrinsic modulators of olfactory coding, a variety of mechanisms make their influence non-uniform.

EXTRINSIC MODULATION OF OLFACTORY PROCESSING
Animals must constantly adjust their sensory processing to meet the ongoing demands of a dynamic internal and external environment. Both insects and vertebrates heavily rely on their sense of smell to find mates, acquire food and avoid harmful threats in their environment. However, the relative importance of different odors varies with current physiological demands. Extrinsic modulatory neurons from other networks can therefore adjust activity within the OB and AL to provide the context of current internal demands of the individual animal. The olfactory system is subject to a number of extrinsic sources of neuromodulation including 5-HT, DA (in some insects), ACh and NE that have been associated with broad physiological states like waking state, aversion, attention and learning/memory (McLean and Shipley, 1987;Mandairon et al., 2006;Matsutani and Yamamoto, 2008;Fletcher and Chen, 2010;Wasserman et al., 2013; but see Linster and Cleland, 2016). Here, we will focus on the effects of 5-HT as both the OB and AL receive 5-HT innervation from extrinsic sources, and there are many similarities between the cellular and molecular features of serotonergic modulation in both networks.

Cell Class Specific Effects of Serotonergic Modulation
In the AL and OB, neuronal class specific 5-HT receptor expression results in relatively heterogeneous effects of 5-HT, even within the same neuronal class. The OB, and in particular, the glomerular layer, receives serotonergic innervation from a large number of Median and Dorsal Raphe neurons (Pinching and Powell, 1971;McLean and Shipley, 1987;Shipley and Ennis, 1996;Gómez et al., 2005;Steinfeld et al., 2015;Suzuki et al., 2015;Muzerelle et al., 2016) and each AL across a wide range of insects typically receives input from one to two serotonergic neurons (Kent et al., 1987;Salecker and Distler, 1990;Wegerhoff, 1999;Ignell, 2001;Dacks et al., 2006;Roy et al., 2007). However, despite the ubiquity of 5-HT in the olfactory systems across taxa, the consequences of serotonergic modulation of olfaction have been remarkably uneven across model systems and behavioral tasks. Pharmacological studies have suggested that 5-HT facilitates odor preference learning in rat pups (McLean et al., 1993(McLean et al., , 1996Langdon et al., 1997;Price et al., 1998;Yuan et al., 2003) and enhances behavioral attraction to sex pheromone in moths (Linn and Roelofs, 1986;Gatellier et al., 2004;Kloppenburg and Mercer, 2008). This work suggests that 5-HT upregulates olfactory sensitivity. However, studies directly manipulating serotonergic neurons or serotonergic signaling in the olfactory system indicate that the role of 5-HT is more complex. For instance, conditionally eliminating tryptophan hydroxylase 2 expression in the raphe of mice, and therefore 5-HT synthesis after olfactory development, had no effect on performance in several general olfactory behavioral assays (Carlson et al., 2016). In Drosophila, suppressing the activity of the serotonergic neurons in the AL (the ''CSDns'') increases CO 2 avoidance, while blocking synaptic transmission decreases sensitivity to the pheromone cVA (Singh et al., 2013), suggesting that the effects of 5-HT can be odor dependent. Furthermore, the CSDns modulate ethanol attraction in concert with other serotonergic neurons that do not innervate the AL (Xu et al., 2016).
Similar to behavioral studies, the physiological effects of 5-HT within the olfactory system are also heterogeneous. Early studies in the rabbit OB showed that application of 5-HT decreased spontaneous firing rate of mitral cells (MCs; Bloom et al., 1964). More recent studies in rats revealed that 5-HT can directly (via the 5-HT2a receptor) and indirectly (via 5-HT2a receptor expression in ETs) excite MCs, yet also increases inhibition exerted upon MCs by depolarizing a subset of juxtaglomerular cells (via 5-HT2c; Hardy et al., 2005;Petzold et al., 2009;Liu et al., 2012;Schmidt and Strowbridge, 2014;Brunert et al., 2016;Huang et al., 2017). Stimulating Raphe input specifically to the OB depolarizes tufted cells (TCs; Kapoor et al., 2016) and has a heterogeneous effect on MC baseline activity (Brunert et al., 2016;Kapoor et al., 2016). However, as discussed below, dual-transmission of glutamate and serotonin by Raphe neurons complicates these findings (Liu et al., 2014). Raphe stimulation also enhances PG and sSA cell (Brunert et al., 2016) and TC responses (Kapoor et al., 2016) to clean and odor laden air. Raphe stimulation appears to predominantly enhance MC odor-evoked responses (Brunert et al., 2016), however this can be odor dependent (Kapoor et al., 2016). Consistent with a theme of heterogeneity, 5-HT was recently demonstrated to excite MCs in the main OB (MOB), yet inhibit MCs in the accessory OB (AOB; Huang et al., 2017). In moths, bath applied 5-HT reduces two K + conductances (Mercer et al., 1995(Mercer et al., , 1996Kloppenburg et al., 1999), enhancing PN and LN excitability resulting in increased odor evoked activity (Kloppenburg et al., 1999;Dacks et al., 2008). However, this only occurs for roughly half of the neurons recorded, and in some instances 5-HT decreases odor evoked responses in an odor-dependent manner (Kloppenburg et al., 1999;Dacks et al., 2008). In Drosophila, bath application of 5-HT enhances PN odor-evoked responses and sensitivity (Dacks et al., 2009;Zhang and Gaudry, 2016). However, pharmacological manipulations demonstrate that endogenous 5-HT reduces PN odor-evoked responses in the AL (Zhang and Gaudry, 2016). Surprisingly, the sole source of serotonergic innervation to the AL (the CSDns) do not affect PN responses to cVA, yet other serotonergic neurons outside the AL do affect cVA responses (Zhang and Gaudry, 2016). These results suggest that the AL can be modulated by both synaptic and non-synaptic sources of 5-HT, perhaps via the hemeolymph, in an odor-dependent manner.
The heterogeneous effects of 5-HT in the olfactory system likely arise due to cell-type specific 5-HT receptor expression and the heterogeneity of serotonergic neurons innervating the AL and OB. There are at least ten 5-HT receptors expressed in the OB (Appel et al., 1990;Hellendall et al., 1993;Shen et al., 1993;Tecott et al., 1993;Watts et al., 1994;McLean et al., 1995;Wright et al., 1995;Waeber et al., 1998;Bai et al., 2004;Lucaites et al., 2005;Petzold et al., 2009) and all five insect 5-HT receptors are expressed in the ALs of Drosophila (Sizemore and Dacks, 2016) and Manduca (Dacks et al., 2013). In Drosophila, each neuronal class expresses a different combination of 5-HT receptors. However, any given receptor is only expressed by a subset of neurons within that class (Sizemore and Dacks, 2016) which likely contributes to the non-uniform effects of 5-HT. Similarly, 5-HT directly enhances MOB MCs via the 5-HT2A receptor, yet inhibits AOB MCs via both the 5-HT1 receptor and enhanced GABAergic transmission to MCs due to 5-HT2 receptor expression by interneurons (Huang et al., 2017). Consequently, complex receptor expression patterns likely play a major role in the observed heterogeneity in the effects of 5-HT. Heterogeneity of serotonergic neurons also likely contribute to the non-uniform effects of 5-HT in the olfactory system. Raphe neurons can release both 5-HT and glutamate (Liu et al., 2014) and only glutamate receptor antagonists block the Raphe-induced depolarization of TCs (Kapoor et al., 2016). Serotonergic neurons innervate different functional zones within the OB (Won et al., 1998;Gómez et al., 2005;Steinfeld et al., 2015) and even different functional zones within glomeruli in Manduca (Sun et al., 1993;Lizbinski et al., 2016). Glomerular specific differences in serotonergic innervation have also been observed in the OB (Gómez et al., 2005), and the processes of the CSDns in Drosophila (Singh et al., 2013). Furthermore, the distribution of CSDn active zones vary widely across glomeruli, yet are highly stereotyped across individual animals (Coates et al., 2017). Thus, even within a single identified modulatory neuron, specific traits can be heterogeneous across compartments. In addition, the CSDns receive network wide inhibition from LNs and glomerulus-specific excitation from OSNs and PNs, indicating that 5-HT modulation cannot be considered purely ''Top-Down'' (Coates et al., 2017). Since the CSDns receive input based on AL network dynamics as well as from other networks, they can be considered partially intrinsic to the AL.
Finally, the circumstances in which 5-HT is released are surprisingly varied (Andrade and Haj-Dahmane, 2013;Dayan and Huys, 2015). The levels of 5-HT in the AL of moths fluctuate throughout the day, peaking when moths are most active (Kloppenburg et al., 1999) reminiscent of daily fluctuations of Raphe neuron activity and 5-HT production (Trulson and Jacobs, 1979;Jacobs and Fornal, 1991;Park et al., 1999;Corthell et al., 2013). Raphe neurons also have a relatively heterogeneous transcriptional profile (Okaty et al., 2015) and individual Raphe neurons can respond to either reward or punishing stimuli (Nakamura et al., 2008;Ranade and Mainen, 2009;Bromberg-Martin et al., 2010;Miyazaki et al., 2011a,b;Nakamura, 2013;Liu et al., 2014;Pollak Dorocic et al., 2014;Weissbourd et al., 2014;Cohen et al., 2015;Hayashi et al., 2015;Li et al., 2016;Luo et al., 2016), as well as display experience dependent plasticity in response properties (Zhong et al., 2017). The heterogeneous nature of serotonergic neurons and the complicated context in which 5-HT is released likely contribute to the non-uniform effects that have been observed for the physiological and behavioral consequences of 5-HT.

METAMODULATION: EXTRINSIC MODULATION OF INTRINSIC MODULATION
Metamodulation, or the modulation of modulation, allows extrinsic neurons to exert global control over already existing intrinsic modulatory circuits (Katz, 1999). Centrifugal neurons that innervate the olfactory system often target LNs and juxtaglomerular neurons (Matsutani and Yamamoto, 2008;Mouret et al., 2009) as an efficient mechanism for altering network processing. Presynaptic inhibition provides powerful, odor-specific control over the dynamic output of the olfactory system. Some studies have suggested that this mechanism may be further modulated via extrinsic inputs in the context of behavioral state (Pirez and Wachowiak, 2008;McGann, 2013). Specifically, widely projecting serotonergic neurons (as detailed above) target sub-populations of LNs to indirectly influence presynaptic activity of OSNs and alter stimulus dependent inhibition. In insects, 5-HT increases lateral GABAergic input to OSNs to adjust GABAb mediated presynaptic gain control (Dacks et al., 2009). In the OB, 5-HT depolarizes ETs via the 5-HT2a receptor, sSAs via 5-HT2c, and indirectly excites both sSAs and PGs via glutamatergic ETs. This increases GABAergic/DAergic modulation onto presynaptic terminals of OSNs, reduces OSN output, and ultimately may reduce M/T firing rate to alter OB output (Petzold et al., 2009;Liu et al., 2012;Brill et al., 2016). Overall, these studies suggest that extrinsic serotonergic modulation exerts global control over olfactory network dynamics, in part, by targeting an intrinsic modulatory network. CONCLUSION 1. Intrinsic presynaptic inhibition expands the dynamic range of output neurons, allowing the olfactory system to encode odors across a wide range of concentrations. 2. Extrinsic modulation adjusts olfactory processing in the AL and OB based on the activity of other neural networks. 3. The integration of both intrinsic and extrinsic neuromodulation merges both history of network activation with global context of physiological state to adjust the broad modulatory tone of the olfactory system as a whole. 4. Intrinsic and extrinsic modulatory mechanisms exert a heterogeneous influence due to complex patterns of modulatory receptor expression, cell-to-cell variability and complex connectivity in the olfactory system.

AUTHOR CONTRIBUTIONS
KML and AMD both conceived of the ideas for this review and co-wrote the manuscript. Author order was determined by degree of caffeination.

ACKNOWLEDGMENTS
We would like to thank Dr. Daniel Wesson, Dr. Sadie Bergeron, Kathryn Allen, Kaylynn Coates and Tyler Sizemore for their helpful feedback on earlier versions of this manuscript. Our goal in this study was to describe a conceptual dichotomy within the context of the olfactory system. For the sake of brevity, we could not cite every relevant study, so we apologize to those individuals whose work we did not discuss. This work was supported by start-up funds from West Virginia University, an R03 DC013997-01 from the National Institutes of Health, and U.S. Air Force grant no. USAFOSR FA9550-17-1-0117 to AMD.