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date: 15 November 2018

The Feeding Network of Aplysia: Features That Are Distinctive and Shared With Other Mollusks

Abstract and Keywords

This review focuses on the neural control of feeding in Aplysia. Its purpose is to highlight distinctive features of the behavior and to describe their neural basis. In a number of mollusks, food is grasped by a radula that protracts, retracts, and hyperretracts. In Aplysia, however, hyperretraction can require afferent activation. Phase-dependent regulation of sensorimotor transmission occurs in this context. Aplysia also open and close the radula, generating egestive as well as ingestive responses. Thus, the feeding network multitasks. It has a modular organization, and behaviors are constructed by combinations of behavior-specific and behavior-independent neurons. When feeding is initially triggered in Aplysia, responses are poorly defined. Motor activity is not properly configured unless responses are repeatedly induced and modulatory neurotransmitters are released from inputs to the central patter generator (CPG). Persistent effects of modulation have interesting consequences for task switching.

Keywords: Aplysia, molluskan feeding, sensorimotor transmission, multitasking, task switching

Feeding is a motivated behavior essential for the survival and well-being of invertebrate and vertebrate animals (e.g., Kupfermann, 1974b; Strand, 1999; Gillette et al., 2000; Watts & Swanson, 2002; Gruninger et al., 2007). This review primarily focuses on the neural control of feeding in the gastropod mollusk, Aplysia californica (Fig. 1). In some regards, feeding in Aplysia is similar to feeding in other mollusks. The purpose of this review, however, is to describe the neural basis of distinctive features of the behavior, focusing on several interesting forms of plasticity. This review will not discuss operant or classical conditioning of feeding responses, which are currently important topics of investigation. These subjects are dealt with in another chapter in this volume.

The Feeding Network of AplysiaFeatures That Are Distinctive and Shared With Other MollusksClick to view larger

Figure 1 The mollusk Aplysia californica.

(Photograph courtesy of Tim Kang)

Aplysia as a Model System

Gastropod mollusks (including Aplysia) have a combination of experimentally advantageous features that as a whole are not found in other organisms (Kupfermann, 1999). For example, they are relatively easy to keep, and they exhibit a number of forms of behavioral plasticity. More important, adults grow to a large size as do their neurons, which can be as large as a millimeter. Consequently, neurons can be individually biochemically characterized and manipulated using intracellular current and voltage-clamp techniques.

A number of molluskan behaviors are currently under investigation, including feeding, which is the subject of this review. Feeding is not seasonal, and it is easily elicited in a laboratory setting. It is mediated by a relatively simple neural network that can be studied in isolation, and in preparations in which the periphery remains attached (e.g., in whole feeding head preparations, or semi-intact preparations; e.g., Willows, 1980; Mcclellan, 1982; Weiss et al., 1986c; Evans & Cropper, 1998; Kabotyanski et al., 2000; Jing & Weiss, 2005; McManus et al., 2012). Consequently, cellular processes can be directly related to behavior.

Feeding Behavior

Feeding has been studied in a number of mollusks, most notably Aplysia (as is described in more detail later), Navanax (Levitan et al., 1970; Cappell et al., 1989a, 1989b), Pleurobranchaea (e.g., Gillette et al., 1978; Mcclellan, 1982, 1983a, 1983b; W. J. Davis et al., 1984; Gillette et al., 2000; Hatcher et al., 2006; Hatcher et al., 2008; Potgieter et al., 2010), Helisoma (Murphy, 2001), Tritonia (Bulloch & Dorsett, 1979b, 1979a), Planorbarius (Brace & Quicke, 1980, 1981), Helix (Peters & Altrup, 1984), Planorbis (Arshavsky et al., 1988a, 1988b, 1988c), Limax (Delaney & Gelperin, 1990a, 1990b, 1990c), Lymnaea (Benjamin & Rose, 1979, 1980; Rose & Benjamin, 1981a, 1981b), and Clione (Norekian & Satterlie, 1993; Norekian, 1993). In Aplysia, feeding has been studied in a number of species, for example, kurodai (Nagahama & Takata, 1987, 1988, 1989, 1990a, 1990b; Nagahama & Shin, 1998; Nagahama et al., 1999; Narusuye & Nagahama, 2002; Narusuye et al., 2005; Kinugawa & Nagahama, 2006a, 2006b, 2006c), fasciata (Susswein et al., 1983, 1984, 1986; Susswein & Schwarz, 1983; Susswein, 1984; Schwarz et al., 1988; Botzer et al., 1991; Schwarz et al., 1991, 1998; Schwarz & Susswein, 1992; Ziv et al., 1991a, 1991b, 1991c), oculifera (Schwarz & Susswein, 1984; Susswein et al., 1986; Schwarz et al., 1988, 1991), depilans (Rose, 1972, 1976), and californica. This review focuses on Aplysia californica (Fig. 1). See Benjamin (2012) and Murphy (2001) for reviews of the neural control of feeding in Lymnaea and Helisoma and W. J. Davis (1985) and Hirayama et al. (2012) for Pleurobranchaea reviews.

Feeding in Aplysia has been divided into appetitive and consummatory phases (Kupfermann, 1974a, 1974b). Appetitive behaviors include locomotion and head movements (e.g., turning and lifting) (Bablanian et al., 1987; Teyke et al., 1990; Nagahama et al., 1993, 1994). During “consummatory” behaviors there are successful or unsuccessful attempts to move food in or out of the buccal cavity. Much current research focuses on the latter class of behaviors, which will be the focus of this review.

Aplysia, like many other mollusks such as Lymnaea and Helisoma, are herbivores (Kupfermann & Carew, 1974). The feeding movements that have been studied differ, however. In Lymnaea and Helisoma food is scraped from a substrate, whereas the behavior that has been most extensively studied in Aplysia is one in which strips, or pieces of seaweed, are ingested (Elliott & Susswein, 2002; Wentzell et al., 2009). Specific behaviors that have been studied in Aplysia include bites, bite-swallows, and swallows (Fig. 2A) (Kupfermann, 1974b).

The Feeding Network of AplysiaFeatures That Are Distinctive and Shared With Other MollusksClick to view larger

Figure 2 Feeding behaviors in Aplysia. (A) Drawing of an Aplysia head with a protracted radula (yellow green) and a strip of food (green). Ingestive behavior is shown in the top row, and egestive behavior in the bottom row. When behaviors are ingestive, radula opening occurs during protraction, and radula closing occurs during retraction. When behaviors are egestive, radula opening occurs during retraction, and radula closing during protraction. (B) A comparison of the duration and phasing of radula movements during three ingestive behaviors (bites, bite-swallows, and swallows) (left) and egestive behavior (right). The three ingestive behaviors differ in the relative durations of protraction and retraction. During a bite and bite-swallow, protraction has a relatively long duration since the radula protracts out of the buccal cavity. During a bite, food is not actually ingested and retraction has a relatively short duration. During a bite-swallow and swallow, food is ingested and retraction has a relatively long duration so that food is deposited in the esophagus. Egestive behaviors are similar to ingestive behaviors in that protraction precedes retraction. There is, however, a phase shift in radula opening and closing.

When animals bite, food is not ingested. Thus, bites are either exploratory or are “unsuccessful” bite-swallows. A bite-swallow results in the ingestion of a single, relatively small piece of food. When animals ingest long strips (or pieces) of seaweed, the initial large movement (bite-swallow) is followed by a series of smaller movements that progressively draw the seaweed into the buccal cavity (swallows). In its natural environment, Aplysia do not appear to feed continuously. Instead, periods of eating are interrupted by periods of rest or other behaviors (Kupfermann & Carew, 1974; Susswein et al., 1983, 1984).

Feeding behaviors can be classified as ingestive or egestive (Fig. 2A, 2B). Much molluskan research has focused on the neural basis of ingestive behavior. Ingestive feeding is triggered when food contacts external structures such as the lips, rhinophores, and tentacles Bovbjerg, 1968; Audesirk, 1975; Bicker et al., 1982b Kemenes et al., 1986). In general, sensory neurons activated are either chemosensitive (Audesirk, 1975; Bicker et al., 1982a) or mechanosensitive (Rosen et al., 1979; Bicker et al., 1982a), and data suggest that cross modality integration is important for the induction of normal behavior (Rosen et al., 1982). Some of the sensory neurons that trigger behavior have somata within the central nervous system (e.g., the cerebral ganglion; Rosen et al., 1979). Other afferents have “peripherally” located cell bodies (Bicker et al., 1982a; Xin et al., 1995).

Mollusks that are capable of egestive behavior include Aplysia (e.g., D. W. Morton & Chiel, 1993a, 1993b; Nagahama & Shin, 1998; Nagahama et al., 1999; Zhurov et al., 2005a; Novakovic et al., 2006; McManus et al., 2012), Helisoma (Murphy, 2001), and Pleurobranchaea (Mcclellan, 1982). In Aplysia, rejection responses can be triggered when an inappropriate object is ingested and cannot be swallowed (Kupfermann & Carew, 1974; D. W. Morton & Chiel, 1993a, 1993b). Additionally, Aplysia can dynamically switch between ingestive and egestive movements when it is behaviorally appropriate, for example, when ingestion is not possible (Proekt et al., 2008). A striking feature of feeding in Aplysia is its variability (e.g., Horn et al., 2004; Brezina et al., 2006; Cullins et al., 2015).

Radula Movements

Many mollusks (including Aplysia) utilize a toothed chitinous structure, known as the radula to ingest food (Fig. 2A) (e.g., Howells, 1942). This structure can move forward or backward in the buccal cavity; that is, it can protract or retract (Fig. 2B). “Retraction” can consist of a backward movement that returns the radula to a neutral position. Additionally, the radula can “hyperretract,” which pushes food further into the buccal cavity (i.e., into the esophagus) (Weiss et al., 1986c). These movements are similar to those that have been described in other mollusks (e.g., Elliott & Susswein, 2002; Wentzell et al., 2009).

Additionally, in Aplysia (and some other mollusks), there is a longitudinal fold in the center of the radula that acts as a hinge and allows the two radula halves to open and close (Howells, 1942; Kupfermann, 1974b; Mcclellan, 1982). The timing of the opening and closing movements as compared to protraction and retraction determines whether behaviors are ingestive or egestive (Fig. 2A, 2B) (D. W. Morton & Chiel, 1993a, 1993b; Church & Lloyd, 1994). Namely, during ingestive behaviors the radula protracts open and retracts closed, which will tend to pull food in. In contrast, during egestive behaviors the radula protracts closed and retracts open, which will tend to push food (or an object) out.

Radula movements primarily result from contractions of the intrinsic muscles of the buccal mass (e.g., Cohen et al., 1978; Scott et al., 1991; D. W. Morton & Chiel, 1993b; Church & Lloyd, 1994; Evans et al., 1996; Hurwitz et al., 1996; Orekhova et al., 2001). In part, radula movements are produced by muscles that are directly attached to it, and the underlying odontophore (e.g., I4, I5, and the I7-I10 complex (Church & Lloyd, 1994; Cohen et al., 1978; Evans et al., 1996; Orekhova et al., 2001)). Additionally, the position of the radula can be altered by the contraction of other muscles (e.g., the I2 muscle (Hurwitz et al., 1996) and the I1/I3 muscles (Sutton et al., 2004; Novakovic et al., 2006; Ye et al., 2006b; Neustadter et al., 2007).

Central Pattern Generation in the Context of Aplysia Feeding

Feeding in Aplysia (and a number of other mollusks) is primarily mediated by neurons in the fused cerebral ganglion and in the two buccal hemiganglia (Fig. 3A) (Kupfermann, 1974a). These neurons control movements of the radula (as well as other structures) used to ingest food (Gardner, 1971). Organized oscillatory activity can be triggered in many of these neurons in the absence of the periphery indicating the involvement of a central pattern generator (CPG) (e.g., Susswein & Byrne, 1988; Plummer & Kirk, 1990; Perrins & Weiss, 1996; Jing & Weiss, 2001).

The Feeding Network of AplysiaFeatures That Are Distinctive and Shared With Other MollusksClick to view larger

Figure 3 Organization of the feeding circuitry in Aplysia. Feeding is primarily mediated by neurons in the cerebral and buccal ganglia (A). Ingestive motor activity is triggered when food activates sensory neurons that excite cerebral buccal interneurons (CBIs) such as CBI-2 (A). CBI-2 activates the feeding CPG, which is in the buccal ganglion (A). Egestive motor activity is triggered when afferents with processes in the esophageal nerve (EN) are activated. EN afferents also activate the feeding CPG (A). The feeding CPG primarily (but not exclusively) consists of interneurons (B). Protraction phase interneurons such as B31/B32 and B63 reciprocally inhibit retraction phase interneurons such as B64 and CBI-5/6. Inputs to the feeding CPG trigger motor activity via direct excitation of the protraction circuitry. Triangles represent excitatory synaptic connections and circles represent inhibitory connections.

It was originally suggested that there are two feeding CPGs that oscillate independently in Aplysia—one in the cerebral ganglion, which controls lip movements, and one in the buccal ganglion, which controls movements of the buccal mass (Perrins & Weiss, 1996). This idea was appealing since the motor neurons that innervate the lips are in the cerebral ganglion (Perrins & Weiss, 1996), whereas the motor neurons that innervate the buccal mass are in the buccal ganglion (Table 1). A subsequent study has however, challenged this idea and strongly suggested that there is only one “distributed” CPG (Jing et al., 2011). In contrast, there is evidence for two independent oscillators in the buccal and cerebral ganglia in Pleurobranchaea (e.g., W. J. Davis et al., 1984). However, this evidence is not yet considered conclusive, since the cerebral oscillator in Pleurobranchaea has not been characterized.

Buccal Motor Neurons and the Feeding Central Pattern Generator

As is typical for other mollusks that have been studied, the buccal central pattern generator (CPG) is primarily, but not exclusively, composed of interneurons (Fig. 3B) (Susswein & Byrne, 1988; Plummer & Kirk, 1990; Hurwitz et al., 1994; Hurwitz & Susswein, 1996; Hurwitz et al., 1997; Kabotyanski et al., 1998; Staras et al., 1998; Jing & Weiss, 2001, 2002; Dembrow et al., 2003; Jing et al., 2004, 2011; Sasaki et al., 2007, 2009, 2013). These interneurons drive motor neurons that innervate structures of the buccal mass and associated digestive structures (e.g., the esophagus and salivary glands) (Fig. 3B). A number of these motor neurons have been identified in Aplysia californica and are listed in Table 1.

Table 1 Identified Motor Neurons in Aplysia californica

Neuron

Muscle Innervated

References

B1

Distal esophagus

Lloyd et al., 1988

B2

Anterior esophagus

Lloyd et al., 1988

B3

I3

Church et al., 1993; Church and Lloyd, 1994

B6

I3, I6

Church and Lloyd, 1994

B7

Hinge muscle

Ye et al., 2006a

B8

Outer I4 leaflets, I6,

Church and Lloyd, 1994; Evans and Cropper, 1998

B9

I3, I6

Church and Lloyd, 1994

B10

I3

D. W. Morton and Chiel, 1993b

B11

I4, I6

Church and Lloyd, 1994; Jordan et al., 1993

B13

I6

Church and Lloyd, 1994

B15

I5

Cohen et al., 1978

B16

I5

Cohen et al., 1978

B31/32

I2

Hurwitz et al., 1994

B38

Anterior I3

Church et al., 1993

B39

I3

Church and Lloyd, 1994

B43

I1

Church and Lloyd, 1994

B44

Inner I4 leaflets

Evans and Cropper, 1998

B47

Inhibitory I3

Church et al., 1993

B48

I7-I10

Evans et al., 1996

B61/B62

I2

Hurwitz et al., 1994

B66

Subradula tissue

Borovikov et al., 2000

B67

Salivary ducts, pharynyx

Serrano et al., 2007

The organization of the Aplysia feeding CPG is modular (Jing & Weiss, 2001, 2002; Jing et al., 2004). For example, one set of neurons controls radula protraction/retraction movements, and a second set controls radula opening/closing movements (Jing & Weiss, 2002). We begin by describing the protraction/retraction circuitry.

Protraction-Retraction Circuitry

In some mollusks (e.g., Lymnaea, Helisoma, Planorbis, and Tritonia) buccal motor patterns have three active phases that mediate protraction, retraction, and hyperretraction (e.g., Bulloch & Dorsett, 1979b; Rose & Benjamin, 1979; Arshavsky et al., 1988a, 1988b, 1988c; Quinlan & Murphy, 1991). These phases have been referred to as N1, N2, and N3, or S1, S2, and S3. Aplysia appears to differ in that the induction of the third phase (hyperretraction) can be observed in vivo and in vitro (D. W. Morton & Chiel, 1993a, 1993b), but it is not always present (as is described in more detail below).

In Aplysia (and other mollusks) there is reciprocal inhibition between protraction and retraction interneurons (Fig. 3B) (Hurwitz & Susswein, 1996; Hurwitz et al., 1997; Sasaki et al., 2007, 2008). Additionally, protraction interneurons provide weak excitatory input to retraction interneurons, which promotes phase shifting (e.g., Jing et al., 2004; Sasaki et al., 2008). Consequently, protraction is generally followed by retraction; that is., once protraction has been initiated, it can be difficult to stop the protraction-retraction sequence (Susswein et al., 2002). The “decision” to initiate a response is, therefore, made when the animal “decides” to protract (Hurwitz et al., 2008).

Radula Protraction and Decision Making

Mechanisms contributing to decision making in the protraction circuitry have been extensively characterized. Protraction is achieved when a sustained plateau-like depolarization is generated in neurons B31/B32 (Susswein et al., 2002). The generation of this plateau is an all-or-none event (Hurwitz et al., 1994; Susswein et al., 2002). B31/B32 are dual function, and are both interneurons and motor neurons (Hurwitz et al., 1994). They innervate the I2 muscle, which protracts the radula (Hurwitz et al., 1996).

In part, B31 and B32 are depolarized by input from other protraction interneurons, notably from the buccal-cerebral interneuron (BCI), B63 (Hurwitz et al., 1997). In part, this input is electrical; that is, B63 and B31/B32 are electrically coupled, creating a positive feedback loop (Hurwitz et al., 1997). Additionally, there is chemical transmission between B63 and B31/32. B63 is a cholinergic interneuron and induces both slow and fast excitatory postsynaptic potentials (EPSPs) in B31/B32 (Hurwitz et al., 2003; Dembrow et al., 2004). The slow (muscarinic) input induces inward currents in B31/B32 (Hurwitz et al., 2008), and it is essential for plateau induction (Dembrow et al., 2004). Thus, plateau generation in B31/B32 is conditional and requires “modulatory” (muscarinic) input.

B31 and B32 are also cholinergic (Hurwitz et al., 2000) and provide positive feedback to themselves via an autapse (Saada et al., 2009). This positive feedback at least in part consists of muscarinic self-excitation (Saada-Madar et al., 2012). Thus, an interesting neural mechanism (an autapse-driven plateau potential) appears to play an important role in protraction “decision making.”

Radula Retraction and Behavior-Dependent Phase Switching

Protraction is terminated when retraction phase interneurons begin to fire and inhibit the protraction interneurons (Fig. 3B). Interestingly, the mechanism utilized to phase-switch depends on the nature of the motor program generated. Namely, the buccal neuron B64 acts as the protraction terminator during ingestive activity (Hurwitz & Susswein, 1996; Sasaki et al., 2008). During egestive activity, however, protraction is regulated by a pair of cerebral-buccal interneurons (CBIs), CBI-5 and CBI-6 (Sasaki et al., 2007, 2008), which can phase advance protraction termination. CBI-5/6 are interesting cells in that they are functionally compartmentalized (Perrins & Weiss, 1998). One compartment includes the soma and is in the cerebral ganglion. The second compartment consists of part of the axon and is in the buccal ganglion. It is the latter compartment that interacts with the buccal CPG.

Afferent-Induced Hyperretraction

In Aplysia motor programs can be induced without a hyperretraction phase. It is most likely that these programs mediate biting behavior; that is, the radula retracts to return to a neutral position but does not move deeply into the buccal cavity. Biting-like motor programs can, however, be modified so that hyperretraction is “added.” This can be accomplished in part by activating sensory neurons, for example, the buccal sensory neuron B21 (Shetreat-Klein & Cropper, 2004). B21 is the largest neuron in a cluster of radula mechanoafferents (RMs) (Rosen et al., 2000). Radula mechanoafferents are peripherally activated when anything (including food) touches the food-grasping portion of the radula (Miller et al., 1994). It has been suggested that the RMs play an important role in triggering bite to bite-swallow conversions, that is, the enhanced radula movements that are necessary if food is to be deposited in the esophagus (Cropper et al., 2004a).

Data strongly suggest that the RMs in Aplysia are homologous to a cluster of sensory neurons in Helisoma (i.e., neurons B101–B104). In particular, neurons in the B101 cluster are also RMs (Wentzell et al., 2009). RMs in Aplysia contain the small cardioactive peptides (SCPs) (Miller et al., 1994), as do neurons in the B101 cluster in Helisoma (Wentzell et al., 2009). The Aplysia neuron B21 is glutamatergic (Klein et al., 2000) as is one of the largest neurons in the B101 cluster in Helisoma (B102) (Wentzell et al., 2009). Finally, neurons in the B101 cluster play an important role in triggering hyperretraction (Wentzell et al., 2009).

Afferent transmission in the Aplysia neuron B21 is regulated so that it occurs in a phase-dependent manner. Thus, the bite-swallow conversion is triggered if sensory neurons such as B21 are peripherally activated during the radula retraction phase of motor programs. Conversions are, however, not triggered if B21 is peripherally activated during protraction (Cropper et al., 2004b). Multiple mechanisms mediate this form of control. One interesting mechanism involves the regulation of spike propagation within the processes of B21 itself (Evans et al., 2003a, 2003b, 2005, 2007, 2008). A second mechanism involves the regulation of the efficacy of synaptic transmission between B21 and follower neurons (Ludwar et al., 2009, 2012).

Hyperretraction can also be “added” to biting-like motor programs by stimulating B51, a dual-function interneuron/sensory neuron (Plummer & Kirk, 1990; Evans & Cropper, 1998; Jing et al., 2004). As a sensory neuron, B51 is peripherally activated when a radula retractor muscle (the I4) contracts (Evans & Cropper, 1998). Afferent activation is particularly pronounced when there is resistance to retraction (Evans & Cropper, 1998). These data suggest that in Aplysia there is a positive feedback system that can adjust the strength of retraction movements so that they are particularly suited to the characteristics of the food that is ingested. To summarize, although biting-like motor programs in Aplysia do not have a hyperretraction phase, these programs can be modified by afferent activation. It is likely that modified motor programs mediate a bite-swallow response.

Hyperretraction in Motor Programs Induced in the Isolated Nervous System

In other situations, hyperretraction is observed in Aplysia when motor programs are triggered in the isolated nervous system (i.e., without the periphery). Whether or not hyperretraction is observed can depend on the means that are used to induce rhythmic activity. For example, when the command-like neuron CBI-2 is used to trigger motor programs, there is generally no hyperretraction (i.e., motor programs are biting-like) (e.g., Jing et al., 2004). In contrast, hyperretraction is common when motor activity is triggered by stimulating a second command-like neuron, CBI-4 (Jing et al., 2004; Sasaki et al., 2013). In this situation, motor programs are swallowing-like, presumably due to the coactivation of B51 and an electrically coupled neuron (B71) (Sasaki et al., 2013). In summary, data suggest that bite-swallows are generated by modifying biting motor programs. Swallows, however, result from the activation of a different command-like neuron.

Additionally, when motor programs are generated in the presence of background stimulation of a peripheral nerve, operant conditioning modifies properties of the sensory/interneuron B51 (as is discussed in more detail elsewhere in this volume) (e.g., Nargeot et al., 1999a, 1999b; Mozzachiodi et al., 2008). B51 is electrically coupled to a number of retraction motor neurons (Plummer & Kirk, 1990; Evans & Cropper, 1998) and increases in B51 activity to induce hyperretraction (Evans & Cropper, 1998). B51 is also a site for the associative memory induced by classical conditioning (Lorenzetti et al., 2006). Thus, it is likely that the probability that hyperretraction will be triggered is at least to some extent determined by the previous history of the system.

Radula Opening and Closing and Multitasking in the Feeding Network

Although radula protraction always precedes radula retraction in Aplysia, radula opening and closing phase-shift to determine whether programs are ingestive or egestive (Fig. 2A, 2B). Consequently, there has been considerable interest in characterizing mechanisms that pattern the activity of the radula opening and closing motor neurons. These mechanisms determine the ability of the feeding network to multitask.

Current data indicate that one of the key motor neurons that mediates radula closing (B8) is active during both ingestive and egestive behaviors (D. W. Morton & Chiel, 1993a, 1993b). In contrast, radula opening is mediated by behavior-specific motor neurons, that is, B48 during ingestive behavior, and B44 during egestive behavior (Friedman et al., 2009). It has been of interest to contrast motor control in these two situations since patterning appears to be mediated by different types of mechanisms. Since the radula opening motor neurons are behavior-specific, selective activation is achieved by direct changes in motor neuron excitability. The excitability of B48 is increased during the induction of ingestive behavior (Friedman & Weiss, 2010), and the excitability of B44 is increased during the induction of egestive behavior (Friedman et al., 2015). In contrast, changes in the timing of the radula closer motor neuron B8 activity are mediated by changes in the excitability of behavior-specific interneurons. Some of the well-characterized interneurons that can pattern B8 activity are listed in Table 2.

Table 2 Interneurons That Pattern B8 Activity

Neuron

Activity Promoted

B4/5

Egestive (Jing & Weiss, 2001)

B20

Egestive (Jing & Weiss, 2001, 2002)

B30

Ingestive—swallow-like (Jing et al., 2004)

B40

Ingestive—bite-like (Jing & Weiss, 2002; Jing et al., 2003; Jing et al., 2004)

B51

Ingestive (Nargeot et al., 1999b); Hyperretraction (Evans & Cropper, 1998; Jing et al., 2004; Sasaki et al., 2013)

B65

Egestive (Due et al., 2004)

B70

Egestive (Sasaki et al., 2009; Sasaki et al., 2013)

B71

Hyperretraction (Sasaki et al., 2013)

Interestingly there is more than one interneuron that can promote a particular type of motor output in B8 (i.e., ingestive or egestive). In part, this is presumably a reflection of the fact that some neurons are active during the protraction phase of motor programs, whereas others are active during retraction. For example, B20 and B4/5 both promote egestive activity. B20 increases B8 activity during protraction (Jing & Weiss, 2001, 2002), and B4/5 decrease it during retraction (Jing & Weiss, 2001). Additionally, B8 activity is, at least in part, controlled by concurrent excitation and inhibition, which results in a high conductance state (Sasaki et al., 2009, 2013). Finally, different neurons appear to be utilized under different conditions. For example, B40 mediates bite-like programs (Jing & Weiss, 2002; Jing et al., 2003), whereas B30 mediates swallow-like programs (Jing et al., 2004). The relative importance of two egestive interneurons (B20 and B65) also appears to vary and be determined by how task switching occurs in the network (as is discussed in more detail later).

Food-Induced Arousal and Neuromodulation

When feeding is repeatedly induced, response latency progressively decreases and bite strength increases (e.g., Susswein et al., 1978). These effects persist and are accompanied by other physiological changes, for example, an increase in blood pressure and heart rate (Koch et al., 1984). This change in state has been referred to as food-induced arousal (Kupfermann, 1974b). Neurons that have been studied in this context are the giant serotonergic neurons. These cells were among the first to be identified as unique individuals in mollusks, and homologous neurons are present in a number of molluskan species (Weiss & Kupfermann, 1976). In Aplysia californica, they are referred to as the metacerebral cells (MCCs). In Lymnaea, they are referred to as the cerebral giant cells (CGCs) (e.g., Yeoman et al., 1994a, 1994b).

In Aplysia, the MCCs receive excitatory input from an identified histaminergic sensory neuron in the cerebral ganglion, C2 (Weiss et al., 1986b). This input does not decrement, and it has interesting properties that characterize it as “modulatory” and make it highly effective as a potential mediator of arousal. C2 is chemosensitive, and it is activated by mechanical stimulation of the perioral zone (Weiss et al., 1986a, 1986c). In semi-intact preparations, seaweed triggers spiking in both C2 and the MCCs, and C2 hyperpolarization reduces the MCC firing frequency (Weiss et al., 1986c). A related and interesting observation is that activity of the MCCs (Jing et al., 2008) and its homolog in Pleurobranchaea (Jing & Gillette, 2000) is also regulated by serotonergic interneurons that drive locomotor behaviors, suggesting that serotonergic neurons in multiple motor networks may act together to promote general arousal (see review by Jing et al., 2009).

Several lines of evidence indicate that the serotonergic giant cells play an important role in the induction of food-induced arousal. For example, MCC activity in Aplysia and CGC activity in Lymnaea is correlated with behavioral arousal in free-moving animals (Kupfermann & Weiss, 1982; Yeoman et al., 1994b). MCC or CGC stimulation potentiates neuromuscular activity (Weiss et al., 1978, 1979), reduces the latency of motor program induction (Proekt & Weiss, 2003), and increases the frequency of motor programs (Yeoman et al., 1994b; Morgan et al., 2000). Serotonin, which is released by the MCCs, exerts second messenger-mediated effects that persist (e.g., Weiss et al., 1979). Finally, deficits in consummatory behaviors are observed in MCC-lesioned animals in Aplysia (Rosen et al., 1983, 1989) and CGC-lesioned animals in Lymnaea (Kemenes et al., 1990). Interestingly, however, although MCC lesions reduce manifestations of food-induced arousal, they do not completely eliminate them.

Other modulators present in the feeding system are neuropeptides. Neuropeptides are present as cotransmitters in multiple classes of neurons, including feeding motor neurons (e.g., Cropper et al., 1987a, 1990b, 1991, 1994; Lloyd et al., 1987; Church & Lloyd, 1991; Church et al., 1993; Evans et al., 1999). Neuropeptides present in the feeding circuit have been referred to as “intrinsic” modulators to distinguish them from the MCCs, which are “extrinsic” to the behavior-generating circuit itself (Cropper et al., 1987b). Neuropeptides are released from motor neurons when they fire at frequencies observed during normal feeding behavior (Cropper et al., 1990a; Vilim et al., 1996a; Vilim et al., 1996b, 2000). In general, their effects are second messenger mediated (e.g., Lloyd et al., 1984; Hooper et al., 1994a, 1994b; Fox & Lloyd, 2000), and a number of peptides potentiate neuromuscular activity (e.g., Cropper et al., 1987a, 1987b, 1991; Evans et al., 1999; Hurwitz et al., 2000; Fox & Lloyd, 2001, 2002). It is therefore likely that at least some of the manifestations of food-induced arousal observed in MCC-lesioned animals result from modulators that are intrinsic to the behavior-mediating neuromuscular systems themselves.

It has been suggested that the two types of modulation (extrinsic and intrinsic) are not redundant. The MCCs are activated during preparatory (appetitive) behaviors, but their activity decreases as animals begin to ingest food (Kupfermann & Weiss, 1982; Rosen et al., 1989; Horn et al., 1999). Although MCC effects persist, they are not likely to be maintained throughout an entire feeding episode. As effects of the MCCs dissipate, consummatory responses are induced and intrinsic modulators are released (Morgan et al., 2000). Thus, it has been suggested that each system has a specialized role, and that the two systems act sequentially to modify feeding behavior (Morgan et al., 2000; Proekt & Weiss, 2003).

Inputs to the Buccal Central Pattern Generator

The Cerebral Buccal Interneurons

Motor programs can be triggered in Aplysia by directly stimulating elements of the CPG (e.g., Susswein & Byrne, 1988; Plummer & Kirk, 1990; Dembrow et al., 2003). Programs can also be triggered by activating CPG inputs (Fig. 3A), for example, cerebral buccal interneurons (CBIs). The CBIs in Aplysia are presumably homologous to the paracerebral neurons in Pleurobranhaea (Gillette et al., 1978), the cerebral ventral 1 cells in Lymnaea (Mccrohan, 1984b, 1984a), and the cerebral buccal cells in Limax (Delaney & Gelperin, 1990a, 1990b, 1990c). CBI-1 in Aplysia californica is likely to be analogous to CBM1 in Aplysia kurodai (Narusuye & Nagahama, 2002).

In Aplysia californica approximately 13 different CBIs have been characterized (e.g., Rosen et al., 1991; Perrins & Weiss, 1998; Hurwitz et al., 1999, 2003; Xin et al., 1999; Wu et al., 2003; Chen et al., 2015). This is similar to the number of CBIs described in other mollusks (e.g., Gillette et al., 1982; Kovac et al., 1983). Some of these neurons are likely to be multiple copies of the “same” cell. This appears to be the case for CBI-5/6 (Perrins & Weiss, 1998) and for CBI-8/9 (Xin et al., 1999). Food clearly activates multiple CBIs, most notably CBI-2, CBI-3, CBI-4, CBI-11, and CBI-12 (Rosen et al., 1991; Jing & Weiss, 2005; Wu et al., 2014). Although there do not appear to be chemical connections between the CBIs, electrical coupling has been described (Xin et al., 1999; Morgan et al., 2002; Wu et al., 2014). It has been suggested that this electrical coupling separates the CBIs into two functional groups, that is, one consisting of CBI-2, CBI-3, and CBI-11, and the other consisting of CBI-12 and CBI-8/9 (Jing et al., 2017). It is, therefore, likely that food activates a group (subset) of the CBIs.

Some of the CBIs are clearly command-like and very effectively trigger motor activity (e.g., Rosen et al., 1991). As is described in more detail later, motor programs that are the most extensively characterized are those that are induced by stimulating CBI-2 (Rosen et al., 1991; Church & Lloyd, 1994; Sanchez & Kirk, 2001). CBI-2 is often used to trigger ingestive activity, since it is activated by food, and with steady-state stimulation it triggers biting-like movements in semi-intact preparations (Rosen et al., 1991; Jing & Weiss, 2005). Parameters of CBI-2-induced motor programs are determined, at least to some extent, by the recruitment of other CBI-s. For example, if CBI-3 is recruited, there is an increase in the degree of ingestiveness of induced activity (Morgan et al., 2002). CBI-2 directly excites protraction interneurons and motor neurons (e.g., Sanchez & Kirk, 2000, 2001; Jing & Weiss, 2002; Hurwitz et al., 2003; Koh et al., 2003; Koh & Weiss, 2005).

A number of the CBIs in Aplysia have been biochemically characterized and contain modulatory neuropeptides that play a critical role in mediating their function. For example, CBI-2, which is cholinergic (Hurwitz et al., 2003), also contains feeding circuit activating peptide (FCAP) (Sweedler et al., 2002; Koh et al., 2003) and cerebral peptide 2 (CP-2) (Morgan et al., 2000). Occlusion experiments have indicated that both peptides play an important role in patterning motor activity (e.g., Friedman & Weiss, 2010). CBI-3 is also peptidergic. It exerts its actions, at least in part, by releasing APGWamide (Jing & Weiss, 2001; Morgan et al., 2002; Sasaki et al., 2009). Finally, CBI-4 contains ATRP, which, like CBI-4, promotes swallow-like programs (Jing et al., 2010).

The Esophageal Nerve

In some mollusks, rejection responses can be triggered by noxious substances (e.g., Mcclellan, 1982; Murphy, 2001), or nonpreferred types of seaweed (e.g., Nagahama & Shin, 1998). In Aplysia californica, however, the response that has been commonly studied is one that occurs when an inappropriate object (e.g., polyethylene tubing) is ingested and makes contact with the esophagus (Kupfermann, 1974b). The esophagus is innervated, at least in part, by one of the buccal nerves, the esophageal nerve (EN) (Kuslansky et al., 1987). This suggests that it should be possible to trigger egestive activity in reduced preparations by electrically stimulating the EN. This was initially attempted in a semi-intact feeding head preparation, and it was indeed noted that EN stimulation induced rejection movements (Chiel et al., 1986). Many subsequent experiments have therefore triggered egestive motor programs in vitro using the EN (Fig. 3A).

It should be noted, however, that the EN is a complex nerve with several branches. Not all branches can be used to induce egestive activity. In fact, as is discussed in more detail elsewhere in this volume, stimulation of one branch (the anterior branch) is used to produce an in vitro analog of operant and classical conditioning (e.g., Nargeot et al., 1997; Lechner et al., 2000a, 2000b; Mozzachiodi et al., 2003). Egestive activity is generally triggered by stimulating the posterior branch of the EN. Stimulation of the EN releases a number of modulatory neuropeptides including SCP (Wu et al., 2010), Aplysia neuropeptide Y (apNPY) (Jing et al., 2007). In addition, FRFamides and FRamides are present in the EN and in the centrally located sensory neurons of the buccal ganglion. These peptides act together to promote egestive programs (Vilim et al., 2010). The egestive programs promoted by these multiple peptides apparently function to reduce food intake in Aplysia (Jing et al., 2007). Interestingly, there are parallels in mammals where a number of “satiety” peptides in the gut are released after a meal and reduce food intake (e.g., Schwartz et al., 2000; G. J. Morton et al., 2006).

Induction of Buccal Motor Programs: Repetition Priming in the Feeding Network

If a single cycle of a buccal motor program is triggered in Aplysia in a rested preparation, radula protraction and retraction are reliably evoked. In contrast, the activity of the radula opening/closing circuitry is not well articulated (Fig. 4A, 4B). For example, the radula closer motor neuron B8 fires at a low frequency during both protraction and retraction (e.g., Proekt et al., 2004, 2007). This is true regardless of the method that is used to trigger motor activity (e.g., whether it is from within the buccal CPG or via a CPG input; i.e., the “ingestive” input CBI-2 or the “egestive” input the EN; Proekt et al., 2004). With repeated input activation, however, program specification can occur (Fig. 4A, 4B). For example, ingestive activity can be triggered by repeated stimulation of CBI-2 (Fig. 4A), and egestive activity by repeated stimulation of the EN (Fig. 4B). However, this is only the case if cycles of motor activity are induced with a relatively short interstimulus interval (ISI) (Cropper et al., 2014).

The Feeding Network of AplysiaFeatures That Are Distinctive and Shared With Other MollusksClick to view larger

Figure 4 Repetition priming in the feeding circuit. Plotted is the mean firing frequency of a radula closer motor neuron (B8) during the radula protraction and retraction phases of motor programs. Cycles of activity were triggered with an ISI of ~ 30 seconds via stimulation of either CBI-2 (A) or the esophageal nerve (EN) (B). Insets are typical intracellular B8 recordings (top trace) and extracellular recordings from buccal nerve 2 (BN2) and the I2 nerve (I2N). Activity in the I2 nerve marks the protraction phase of the motor program. Note that in both cases the first cycle that was triggered was poorly articulated. B8 fired at a relatively low frequency during both the protraction and retraction phases of the motor program (cycle 1 in both A and B). With repeated input activation, however, program definition occurred. For example, with repeated stimulation of CBI-2, motor activity became clearly ingestive (e.g., the B8 firing frequency during retraction was increased) (A). With repeated stimulation of the EN, motor programs became egestive (e.g., the B8 firing frequency during protraction increased (B).

Data are replotted from Friedman et al., (2009) and Friedman and Weiss (2010).

This phenomenon has been referred to as repetition priming since evoked movements are progressively altered as program specification occurs (e.g., Zhurov et al., 2005b; Friedman & Weiss, 2010). Movements are relatively weak and ineffective when activity is first induced (Zhurov et al., 2005b; Friedman et al., 2009). The firing frequency of motor neurons is relatively low, and antagonistic motor neurons are coactive. With repeated input activation, however, phase relationships are defined and motor neurons fire at frequencies that are sufficient to produce effective radula movements (Zhurov et al., 2005b; Friedman et al., 2009). Further, triggered movements are now “appropriate.” For example, CBI-2 is activated by food (Rosen et al., 1991). With repeated stimulation, CBI-2 triggers radula movements that will effectively move food into the buccal cavity (Friedman et al., 2009).

Data strongly suggest that modulatory neurotransmitters released by inputs to the CPG play an essential role in the induction of repetition priming. For example, repetition priming is not observed when motor programs are repeatedly triggered from within the buccal CPG itself (i.e., by stimulating an element of the buccal CPG) (Siniscalchi et al., 2016). There is no repetition priming in this situation even when programs are induced with a relatively short ISI. Further, exogenous application of neuropeptides contained in the CPG inputs mimics and occludes effects of priming (e.g., Friedman & Weiss, 2010; Dacks & Weiss, 2013; Friedman et al., 2015).

Neurotransmitters that induce repetition priming exert second messenger–mediated effects that persist for tens of seconds (e.g., Friedman & Weiss, 2010; Friedman et al., 2015). It has been suggested that this at least partially accounts for the fact that progressive alterations in neural activity are observed as priming develops (Cropper et al., 2014). When cycles of motor programs are repeatedly induced, summation can occur and the magnitude of induced effects can become progressively larger. This would also account for the fact that a relatively short ISI is required for priming. Interestingly, the modulators (and second messenger systems) that mediate ingestive repetition priming appear to differ from those that mediate egestive repetition priming. Thus, there appears to be distinct “chemical coding” for different forms of repetition priming (Friedman et al., 2015).

Task Switching in the Feeding Network

The fact that repetition priming is at least in part mediated by persistent effects of modulatory neurotransmitters potentially has interesting consequences for task switching. Thus, it would be predicted that repetition priming of one type of response (e.g., ingestive or egestive) would “bias” the induction of the other type. This is, in fact, the case, and, as might be expected, this biasing can be “negative” (Fig. 5A) (Proekt et al., 2004). This is true when egestive repetition priming is followed by an attempt to induce ingestive activity. For example, after repeated motor program induction using the EN, stimulation of CBI-2 induces a fully egestive motor program. In a rested preparation, CBI-2 triggers “intermediate” (poorly defined) motor activity.

The Feeding Network of AplysiaFeatures That Are Distinctive and Shared With Other MollusksClick to view larger

Figure 5 Negative biasing in the feeding network. (A) Motor programs were induced by repeated stimulation of the EN with a short ISI (to induce egestive repetition priming). As expected, the last cycle of activity was fully egestive (black triangle). Programs were then triggered by stimulating CBI-2 once a minute. Immediately after EN stimulation the first CBI-2-induced cycle remained in the egestive cluster (orange circle; CBI-2, 0 min). With repeated stimulation, CBI-2 programs returned to the ingestive cluster (orange circles; CBI-2, 1, 2, 3, 4, and 5 min). Data are replotted from Proekt et al. (2004). (B) During EN induced repetition priming, there is an increase in the excitability of B20 and use-dependent potentiation of B20-B8 synaptic transmission (green). Additionally, there is a decrease in the excitability of B40 (red). When cycles of activity are induced by subsequent stimulation of CB-2, negative biasing is observed. CBI-2 makes a fast excitatory connection with B20 and increases its protraction phase firing frequency. This results in increased protraction phase drive to B8. Additionally, CBI-2 less effectively activates B40 (as a result of its decreased excitability). This results in less inhibition in B8 during protraction and less excitation during retraction (an egestive pattern of activity).

Experiments that have sought to determine why negative biasing occurs have demonstrated that it is at least partially due to alterations in the excitability of two interneurons that pattern B8 activity, a dopaminergic neuron, B20 (Teyke et al., 1993), and a GABAergic neuron, B40 (Fig. 5B) (Jing et al., 2003). B20 promotes an egestive pattern of B8 activity, and B40 an ingestive pattern (Jing & Weiss, 2001, 2002; Jing et al., 2003, 2004). Both interneurons are activated during CBI-2-induced motor programs, but in a rested preparation, the excitability of B20 is relatively low and the excitability of B40 is relatively high. Consequently, B40 activity “predominates” when motor activity is triggered. During EN-induced repetition priming, there are excitability changes in both B20 and B40 (Fig. 5B, left). The excitability of B20 is increased and the excitability of B40 is decreased (Proekt et al., 2007). Additionally, there are changes in the efficacy of synaptic transmission, that is, a facilitation of B20-B8 synaptic transmission (Proekt et al., 2004) and a suppression of synaptic transmission between B40 and B8 (Proekt et al., 2007). Consequently when motor programs are triggered after EN stimulation, the B20 firing frequency is relatively high and B20-B8 synaptic transmission is potentiated. B8 activity is, therefore, egestive (Fig. 5B, right).

Interestingly, biasing in the feeding network is not always “negative.” It can also be “positive” (Proekt et al., 2008; Dacks & Weiss, 2013). Positive biasing is observed when CBI-2-induced ingestive priming is followed by an attempt to induce egestive activity using the EN (Dacks & Weiss, 2013). In this situation, the EN triggers fully egestive motor programs instead of the poorly articulated “intermediate” activity that it triggers in a rested preparation.

Circuit-level analyses have demonstrated that positive biasing is a consequence of the fact that there is “degeneracy” in the feeding network in that there is more than one set of “egestive” circuit parameters. Thus, there is a second type of “egestive” interneuron B65. During CBI-2-induced repetition priming, the excitability of B65 is increased (Fig. 6A) (Dacks & Weiss, 2013). It is somewhat surprising that this does not have a negative impact on the induction of ingestive activity. This interesting arrangement is a consequence of the fact that B65 does not receive fast excitatory synaptic input when programs are triggered by CBI-2. Instead, B65 is directly inhibited (Fig. 6A) (Jing & Weiss, 2005). To summarize, although the B65 excitability is increased during ingestive priming (when programs are triggered by CBI-2), this is a “latent” effect that is not immediately expressed since B65 is not excited but is inhibited, and therefore is not a participant in CBI-2 elicited motor programs.

The Feeding Network of AplysiaFeatures That Are Distinctive and Shared With Other MollusksClick to view larger

Figure 6 Positive biasing in the feeding network. (A) During CBI-2-induced repetition priming, there is an increase in the excitability of B65 (green). B65 is, however, not activated (grey) because it is inhibited by CBI-2. (B) When cycles of activity are induced by subsequent stimulation of EN, positive biasing is observed. EN afferents make a fast excitatory connection with B65, which fires at a relatively high frequency (as a result of the excitability increase that occurs when CBI-2 is stimulated). B65 makes a fast excitatory connection with B8 and increases its protraction phase firing frequency.

When there is a switch in input activation, however, the effect on B65 excitability is now manifested (Fig. 6B). This is a result of the fact that B65 does receive fast excitatory synaptic input when programs are triggered by EN stimulation (Fig. 6B). Consequently, when programs are triggered by the EN after ingestive priming, the B65 firing frequency is higher than it would have been without ingestive priming. The CBI-2-induced increase in B65 excitability has been referred to as “latent modulation” (Dacks & Weiss, 2013). Thus, these data experimentally confirm results of a recent modeling study conducted in the crustacean stomatogastric system that demonstrated the importance of fast synaptic transmission for determining whether or not modulation impacts network output (Gutierrez & Marder, 2014). A question that Aplysia research addresses is why a neuron is modulated if network output is not immediately altered. These data suggest that it can have important consequences for the induction of a subsequent behavior, that is, task switching.

Summary

In summary, this review focuses on the neural control of feeding in Aplysia. Aplysia has the experimentally advantageous features common for mollusks, for example, large reidentifiable neurons that can be biophysically characterized and individually manipulated with electrophysiological techniques. Although consummatory behaviors are in some respects typical for mollusks, in other respects behaviors differ. For example, at least in some circumstances radula hyperretraction requires afferent activation triggered either by food contact and/or an increase in resistance to retraction. Afferent-induced modifications of centrally generated motor programs have been characterized and mediating mechanisms described.

Aplysia is a mollusk that can open and close the radula, which makes it capable of egestive as well as ingestive responses. Consequently, it is an ideal model system for studies of multitasking in a network that has a modular organization. Much progress has been made in experiments that have determined how behavior can be constructed by combining the activity of behavior-specific and behavior-independent neurons.

Finally, when feeding behaviors are initially triggered in Aplysia, they are poorly defined (e.g., antagonistic motor neurons are coactive). Behavior definition only occurs when responses are repeatedly induced with a relatively short intervening interval. This is apparently a consequence of the fact that motor activity is configured as a result of the release of modulatory neurotransmitters from inputs to the feeding central pattern generator. As might be expected, persistent effects of modulation impact task switching and, under some circumstances, tend to impede it. Somewhat surprisingly, however, recent research in Aplysia has demonstrated that this is not always the case.

In conclusion, studies of the neural basis of feeding have made important contributions to our understanding of sensorimotor integration during ongoing motor activity, and how multitasking can be achieved in a relatively simple system. Further, neural mechanisms that mediate repetition priming and influence task switching have been described.

Future Directions

  1. 1. Aplysia californica are capable of generating other forms of feeding behaviors (e.g., rasping) that have not yet been studied in detail (Kupfermann, 1974b). In a similar vein, the physiological role of some of the neurons that very effectively trigger feeding motor programs has not been determined. More extensive research is needed to fully recognize the extent to which the Aplysia feeding network multitasks.

  2. 2. A striking characteristic of feeding in Aplysia is its variability. As research in this field progresses, potential sources of this variability have become apparent. For example, it has become increasingly apparent that the preexisting state of the network plays an important role in determining the nature of the output at any given time. Although some contributing factors have been described, there are clearly others yet to be identified.

  3. 3. This review focuses on the neural control of feeding in Aplysia. It is, however, becoming increasingly apparent that an additional source of behavioral multifunctionality is the flexibility of the periphery (e.g., Sutton et al., 2004; Novakovic et al., 2006; Ye et al., 2006a, 2006b). In future research, it will be important to determine how the nervous system exploits this flexibility.

Acknowledgments

The work was supported by the National Institutes of Health (grants NS066587, NS070583, and MH051393).

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