Amygdala Neurons Differentially Encode Motivation and Reinforcement

“Numbers on the left indicate the anteroposterior coordinates caudal to bregma (Paxinos and Watson, 1998).”

“incentive and a reinforcer for different behavioral or environmental contingencies (Everitt and Robbins, 2005).”

“In contrast, a conditioned incentive is defined as a neutral stimulus that acquires motivating properties when associated with primary reinforcement, measured by behaviors such as conditioned approach (Berridge and Robinson, 2003).”

“For example, the BLA has robust reciprocal projections with the medial prefrontal cortex (mPFC) (Vertes, 2004).”

“…cocaine addicts produces intense drug craving (O’Brien et al., 1998), physiological arousal, including increased heart rate and skin conductance (Childress et al. 1988; Ehrman et al. 1992), and amygdala activation (Childress et al. 1999), all of which may lead to a relapse of drug-seeking behavior.”

“Because there is evidence that distinct populations of BLA neurons encode appetitive and aversive stimuli (Paton et al., 2006), it is likely that these neurons have different projections and that the function of the BLA lies in the absolute valence of the outcomes predicted by sensory stimuli, and…”

“In addition, the BLA sends inputs to the nucleus accumbens core (Kelley et al., 1982; Wright et al., 1996), and it has been reported that these connections are important for performing second-order conditioned responses (Setlow et al., 2002).”

“DOI:10.1523/JNEUROSCI.5281-06.2007 Copyright © 2007 Society for Neuroscience 0270-6474/07/273937-09$15.00/0 spond to sensory stimuli paired with positive or negative outcomes (Quirk et al., 1995; Uwano et al., 1995).”

“In agreement with a role for the BLA in conditioned reinforcement (Cador et al., 1989), the second population of cueresponsive neurons maintained their cue response while instrumental responding continued, perhaps reflecting the conditioned-reinforcing properties of the reward-paired cue that can motivate continued no…”

“This phenomenon is called cue-induced reinstatement and is an animal model for relapse to rewardseeking behavior (Epstein et al., 2006).”

“The nucleus accumbens has been suggested as a “final common pathway” for all types of reinstatement (cue-induced, drug-induced, stressinduced) (Kalivas and McFarland, 2003).”

“Lesion studies show that the BLA is important for outcome-specific incentive processes (Balleine et al., 2003; Corbit and Balleine, 2005).”

“…orbitofrontal cortex (OFC), which is reciprocally connected to the BLA (Kita and Kitai, 1990; Shi and Cassell, 1998), is thought to work in coordination with the BLA to use incentive information to guide behavior (Gallagher and Schoenbaum, 1999; Schoenbaum et al., 1999, 2003; Baxter et al., 2000).”

“…orbitofrontal cortex (OFC), which is reciprocally connected to the BLA (Kita and Kitai, 1990; Shi and Cassell, 1998), is thought to work in coordination with the BLA to use incentive information to guide behavior (Gallagher and Schoenbaum, 1999; Schoenbaum et al., 1999, 2003; Baxter et al., 2000).”

“The basolateral amygdala complex (BLA) is critically involved in the formation and expression of associations between sensory cues and rewarding or aversive stimuli (Davis, 1992; LeDoux, 1996; Gallagher, 2000; McGaugh, 2002).”

“It has been shown that lesions of either the BLA or OFC alter the neural encoding of information about expected outcomes and acquired value (Schoenbaum et al., 2003; Saddoris et al., 2005).”

“…cocaine addicts produces intense drug craving (O’Brien et al., 1998), physiological arousal, including increased heart rate and skin conductance (Childress et al. 1988; Ehrman et al. 1992), and amygdala activation (Childress et al. 1999), all of which may lead to a relapse of drug-seeking behavior.”

“BLA lesions attenuate responding to a cue associated with sexual reinforcement but do not alter sexual behavior itself (Everitt et al. 1989).”

“8) is reminiscent of studies done with extinction of cue-shock associations (Repa et al., 2001).”

“The mPFC is also important for cue-induced reinstatement of reward-seeking behavior (McLaughlin and See, 2003).”

“The basolateral amygdala complex (BLA) is critically involved in the formation and expression of associations between sensory cues and rewarding or aversive stimuli (Davis, 1992; LeDoux, 1996; Gallagher, 2000; McGaugh, 2002).”

“This evidence suggests that BLA function is specific to reinforcing properties of the reward-associated cue and does not affect reinforcing properties of the reward itself (Balleine et al., 2003).”

“The orbitofrontal cortex (OFC), which is reciprocally connected to the BLA (Kita and Kitai, 1990; Shi and Cassell, 1998), is thought to work in coordination with the BLA to use incentive information to guide behavior (Gallagher and Schoenbaum, 1999; Schoenbaum et al., 1999, 2003; Baxter et al.,…”

“Evidence suggests that the mPFC regulates the responsiveness of BLA neurons to odor cues previously associated with footshock (Rosenkranz et al., 2003).”

“…that the BLA is a site for the neural representation of reward-associated cues that induce reinstatement to reward-seeking behavior, consistent with studies showing that the BLA is critically involved in cue-induced reinstatement (Meil and See, 1997; Fuchs and See, 2002; Yun and Fields, 2003).”

“Importantly, it has been shown that varying with- drawal periods can affect extinction behavior and the degree to which cueinduced reinstatement is expressed (Grimm et al., 2002; Myers et al., 2006).”

“In addition, the BLA sends inputs to the nucleus accumbens core (Kelley et al., 1982; Wright et al., 1996), and it has been reported that these connections are important for performing second-order conditioned responses (Setlow et al., 2002).”

“…stimulus that acquires reinforcing properties when associated with primary reinforcement, and conditioned reinforcement can be measured by the ability of the cue to support instrumental responding in the absence of the primary reinforcer (Arroyo et al., 1998; Everitt and Robbins, 2000, 2005).”

“Studies have shown that pyramidal neurons and interneurons can be differentiated by both morphological and electrophysiological characteristics (Washburn and Moises, 1992; Rainnie et al., 1993).”

“…stimulus that acquires reinforcing properties when associated with primary reinforcement, and conditioned reinforcement can be measured by the ability of the cue to support instrumental responding in the absence of the primary reinforcer (Arroyo et al., 1998; Everitt and Robbins, 2000, 2005).”

“Rats readily lever press to self-administer primary reinforcers, such as sucrose, cocaine, or alcohol, and subsequently to obtain reward-paired cues in the absence of reward (Davis and Smith 1976; Meil and See 1997; Grimm et al. 2002; Nie and Janak, 2003).”

“…bursts per second, and percentage of total spikes that occur in bursts in the BLA neurons of the paired group as compared with the unpaired group (Table 2) suggest that the reward-paired cue may induce bursting of BLA neurons and are consistent with the study done by Laviolette et al. (2005).”

“It has been shown that lesions of either the BLA or OFC alter the neural encoding of information about expected outcomes and acquired value (Schoenbaum et al., 2003; Saddoris et al., 2005).”

“…that the BLA is a site for the neural representation of reward-associated cues that induce reinstatement to reward-seeking behavior, consistent with studies showing that the BLA is critically involved in cue-induced reinstatement (Meil and See, 1997; Fuchs and See, 2002; Yun and Fields, 2003).”

“Studies have shown that pyramidal neurons and interneurons can be differentiated by both morphological and electrophysiological characteristics (Washburn and Moises, 1992; Rainnie et al., 1993).”

“DOI:10.1523/JNEUROSCI.5281-06.2007 Copyright © 2007 Society for Neuroscience 0270-6474/07/273937-09$15.00/0 spond to sensory stimuli paired with positive or negative outcomes (Quirk et al., 1995; Uwano et al., 1995).”

“Electrophysiological characterization of neuronal response types Pyramidal projection neurons compose 95% of the neurons in the BLA, the remainder being interneurons (McDonald 1982, 1984).”

“In addition, the BLA sends inputs to the nucleus accumbens core (Kelley et al., 1982; Wright et al., 1996), and it has been reported that these connections are important for performing second-order conditioned responses (Setlow et al., 2002).”

“Rats readily lever press to self-administer primary reinforcers, such as sucrose, cocaine, or alcohol, and subsequently to obtain reward-paired cues in the absence of reward (Davis and Smith 1976; Meil and See 1997; Grimm et al. 2002; Nie and Janak, 2003).”

“Rats readily lever press to self-administer primary reinforcers, such as sucrose, cocaine, or alcohol, and subsequently to obtain reward-paired cues in the absence of reward (Davis and Smith 1976; Meil and See 1997; Grimm et al. 2002; Nie and Janak, 2003).”

“…that the BLA is a site for the neural representation of reward-associated cues that induce reinstatement to reward-seeking behavior, consistent with studies showing that the BLA is critically involved in cue-induced reinstatement (Meil and See, 1997; Fuchs and See, 2002; Yun and Fields, 2003).”

“…orbitofrontal cortex (OFC), which is reciprocally connected to the BLA (Kita and Kitai, 1990; Shi and Cassell, 1998), is thought to work in coordination with the BLA to use incentive information to guide behavior (Gallagher and Schoenbaum, 1999; Schoenbaum et al., 1999, 2003; Baxter et al., 2000).”

“from the present meta-analysis provide strong evidence that the amygdala is equally sensitive to rewarding stimuli, as confirmed by a wealth of animal studies (Sugase-Miyamoto and Richmond, 2005; Tye and Janak, 2007; Bermudez et al., 2012).”

“This is consistent with the idea that the amygdala encodes the motivational value of CSs, whether they are acting as a cue to expect reward, or as secondary reinforcers — stimuli that have acquired the ability to act as rewards for instrumental behaviors — as suggested by Tye and Janak [85].”

“…this idea, BLA neurons fire in response to reward-predictive cues during learning (Ambroggi et al., 2008; Paton et al., 2006; Schoenbaum et al., 1999; Tye and Janak, 2007; Uwano et al., 1995) and in anticipation of reward in an olfactory instrumental discrimination task (Schoenbaum et al., 1998).”

“This is what would be expected if the amygdala reports information about the pavlovian motivational significance of the CSs (Tye and Janak, 2007) but is upstream of the processes actually controlling moment-bymoment choices of whether or not to grip; indeed, just such an organization is suggested…”

“BLA neurons are also important for reward-based learning and memory (Beyeler et al., 2016; Gore et al., 2015; Namburi et al., 2015; Tye and Janak, 2007; Tye et al., 2008).”

“Studies in rodents have shown that the basolateral amygdala is critical to learning representations linking stimuli to the incentive values of outcomes (4, 34).”

“, 1995; Vertes and Hoover, 2008), regions known to regulate reward seeking (Ambroggi et al., 2008; Knapska et al., 2013; Mahler and Berridge, 2009; Robinson et al., 2014; Tye and Janak, 2007).”

“That BLA¡OFC projections are vital for cue-triggered reward expectations is consistent with evidence that reward cues activate BLA neurons (Paton et al., 2006; Tye and Janak, 2007; Ambroggi et al., 2008; Sangha et al., 2013; Beyeler et al., 2016) and that the OFC specializes in stimulus– outcome representations (Ostlu…”

“, 2013) and during response execution and inhibition (Tye and Janak, 2007; Tye et al., 2010).”

“BLA pyramidal neurons play a critical role in the processing of emotional information by assigning value to sensory cues and transmitting this signal onto efferent structures to regulate behavioral output in an adaptive manner (Tye and Janak, 2007; Namburi et al., 2015).”

“…respond to the presentation of rewarding stimuli with phasic bursts of action potentials that strongly resemble those produced by SD neurons in response to tastes (Mirenowicz and Schultz, 1996; Pratt and Mizumori, 1998; Schultz, 2001; Paton et al., 2006; Roesch et al., 2007; Tye and Janak, 2007).”

“The basolateral amygdala (BLA) complex is critical for assigning motivational significant to discrete stimuli (Ito et al. 2006; Tye and Janak 2007; Tye et al. 2008), whereas the hippocampus is well-recognized for its role in contextual (Maren and Holt 2000) and spatial processing (Ito et al.”

“The amygdala and hippocampus potently influence learning and memory (Robbins et al, 2008), responses to motivationally important cues (Tracy et al, 2001; Tye and Janak, 2007), and the development and expression of habit-like behaviors (Lingawi and Balleine, 2012).”

“and is important for the acquisition and retrieval of stimulus-outcome memorie”

“…reward seeking (Cador et al., 1989; Baxter and Murray, 2002; Carelli et al., 2003; McLaughlin and See, 2003; McLaughlin and Floresco, 2007; Tye and Janak, 2007; Tye et al., 2008), we hypothesized that BLA neurons encode the change in outcome expectation that underlies the extinction of…”

“2003) as well as in response to cues associated with natural rewards such as sucrose (Tye and Janak 2007).”

“Animal models of reward processing have demonstrated that there are separable neural pathways associated with CPA and APA [ 2 , 8 ].”

“Worth considering is the possibility that the effects of photoactivation may be mediated, at least in part, through facilitation of extinction learning, particularly given the role of the BLA in encoding reward-related cues and extinction of appetitive behavior (Tye and Janak, 2007; Tye et al., 2010).”

“Specifically, exposure to rewardconditioned cues activates a portion of BLA and NAc neurons sequentially (34, 35), while preventing activation of cocainesensitive NAcSh MSNs after withdrawal from cocaine selfadministration attenuates cue-induced cocaine reinstatement (36).”

“…of CU traits, which includes excessive deployment of cognitive resources towards positive and motivationally salient stimuli (Frick and Viding, 2009; Sadeh and Verona, 2008), and is consistent with the role of BLA in motivational salience processing (Dwyer and Killcross, 2006; Tye and Janak, 2007).”

“In support of such a conjecture, neural activity in the VTA and amygdala changes in accordance with the motivational level.(81) Considering the extensive interconnections of iHP with VTA and amygdala,(43,44) the dramatic changes in motivational significance well known to be detected in VTA and amygdala may be directly…”

“…behavior in appetitive tasks can correspond with distinct neuronal activity depending on whether port-entries were made during or outside of a reward cue (Lansink et al, 2012; Tye and Janak, 2007), suggesting that cue-triggered and ITI port-entries may be qualitatively distinct behaviors.”

“…et al. 2008), it also supports other functions related to associative learning, such as signaling attention to salient cues, uncertainty about outcome probability, and intensity of stimuli (Morrison et al. 2011; Saddoris et al. 2005; Tye and Janak 2007; Tye et al. 2010; Belova et al. 2007).”

“Importantly, electrophysiological studies have revealed that BLA neurons are responsive to reward-predictive cues (Tye et al.,, Carelli et al., 2003, Saddoris et al., 2005, Paton et al., 2006, Tye and Janak, 2007, Ambroggi et al., 2008).”

“For EEG recordings, we implanted stainless steel screws (P0090CE125; J.I. Morris) bilaterally into the frontal and parietal bones (1.5 mm anterior and 1.5 mm lateral to bregma; 2 mm posterior and 2.75 mm lateral to bregma).”

“…the remainder of the communication sounds in our stimulus set may reflect their participation in a diverse set of efferent pathways, which may include appetitive behavior and anticipation of reward (Paton et al. 2006; Schoenbaum et al. 1999; Sugase-Miyamoto and Richmond 2005; Tye and Janak 2007).”

“, 2011; Sadeh and Verona, 2008; Sellbom and Verona, 2007], and is consistent with the role of BLA in processing motivational salience [Dwyer and Killcross, 2006; Tye and Janak, 2007].”

“…al., 2009; Floresco et al., 2008b; Ghods-Sharifi et al., 2009; Hosking et al., 2014; Ishikawa et al., 2008; Jimura et al., 2013; McClure et al., 2004; Samanez-Larkin et al., 2011; Smith et al., 2016; Stalnaker et al., 2009; Tye and Janak, 2007; Wassum and Izquierdo, 2015; Winstanley et al., 2004).”

“First, how does increased BLA-mediated neuronal activity during CS presentation influence respectively, CS-evoked conditioned behaviors and the instrumental pursuit of CS? BLA neurons fire in response to CS presentations during appetitive conditioning (Tye and Janak, 2007; Ambroggi et al., 2008; Tye et al., 2008).”

“For lower density brain regions, unit sorting is often done using a combination of template matching and autocorrelation of spike times recorded using twisted electrode bundles [8–10].”

“This neuronal activation supplies cognitive systems with information regarding the motivational and reinforcing qualities of an associated cue that help determine, plan, and execute the appropriate behavioral response (Tye and Janak, 2007).”

“…in the AT network. deactivation in rodents has been shown to decrease reward-seeking behaviors in response to a cue (Ishikawa, Ambroggi, Nicola, & Fields, 2008) and the activity of neurons in the amygdala to a cue stimulus has been linked to motivated, rewardseeking behaviors (Tye & Janak, 2007).”

“This dissociation is notable because single-unit activity and blood oxygenation level-dependent response in both OFC and ABL represent information about expected outcomes (Schoenbaum et al., 1998; Tremblay and Schultz, 1999; O’Doherty et al., 2002; Gottfried et al., 2003; Padoa-Schioppa and Assad, 2006; Paton et al.,…”

“…the BLA respond to Pavlovian cues and to discriminative stimuli that signal the availability of an action to produce reward (Paton et al., 2006; Tye and Janak, 2007; Ambroggi et al., 2008; Morrison and Salzman, 2009; Shabel and Janak, 2009; Sangha et al., 2013), but whether or how they encode…”

“BLA pyramidal neurons fire a burst of action potentials in response to stimuli with strong emotional valence (Nishijo et al., 1988; Tye and Janak, 2007; Motanis et al., 2014).”

“…a role for BLA neurons in mediating opiate reward processes include its role in altering sensory properties (Fontanini et al., 2009), learned reward associations (Schoenbaum et al., 1998; Tye and Janak, 2007) and taste reactivity and consumption behaviors (Berridge, 1996; Will et al., 2009).”

“Relatively unstable ensemble activity related to the same context in the NS and IS mice suggests that arousal, state, and/or unknown factors that change between sessions also affect amygdala activity (Pelletier et al., 2005; Tye and Janak, 2007).”

“Neurons in the BLA respond to cues that have been paired with rewards [41,42] and lesions to this region attenuate cue-induced responding [43].”

“, 2008) that respond to cues predicting either appetitive or aversive outcomes (Paton et al., 2006; Tye and Janak, 2007).”

“For example, cell firing in both OFC and ABL tends to track learning, increasing when cues are paired with reward and decreasing when they are unre-warded 16–21 .”

“decision-making [8,35–40].”

“stress the role of learning and demonstrate that the amygdala is a critical brain structure involved in fearful and appetitive responses to conditional stimuli, including their extinction and reinstatement”

“In behaving animals, BLA neurons tend to be activated in a population-specific manner in response to US versus CS as well as stimuli with different valences, suggesting the functional and populational heterogeneity of BLA neurons ( O’Neill et al., 2018 ; Paton et al., 2006 ; Tye and Janak, 2007 ).”

“66,67 Furthermore, neurons in the amygdala, as well as dopaminergic neurons, have been shown to respond to fully predictable rewards.”

“Arousal refers to the psychological state of wakeful attention and is important for detection of salience, or the relative importance and novelty of stimuli (LaBar and Cabeza, 2006; Uddin, 2017).”

“We next conducted extinction of cue discrimination ( Fig”

“Distinct populations of cue-responsive neurons in the amygdala encode the motivational and reinforcing properties of cues previously associated with rewards (Tye & Janak, 2007).”