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Approach and Avoidance Processing: Investigating a Rostrocaudal Gradient in the Nucleus Accumbens Core
by
Laurie Hamel
A thesis submitted in conformity with the requirements for the degree of Master of Arts
Department of Psychology University of Toronto
© Copyright by Laurie Hamel 2015
Approach and Avoidance Processing: Investigating a
Rostrocaudal Gradient in the Nucleus Accumbens Core
Laurie Hamel
Master of Arts
Department of Psychology University of Toronto
2015
Abstract
The nucleus accumbens is a site of integration of positively and negatively valenced information.
While a rostrocaudal topographical gradient in valence processing has been found in the
accumbens shell, a potential gradient has not fully been explored in the core in relation to its role
in motivation in response to conditioned cues. In the current study, rats were trained to associate
visual cues with appetitive, aversive and neutral outcomes. In a test of motivational bias, the
aversive and appetitive cues were superimposed in a maze arm and rats’ exploratory bias was
measured for this arm vs. a neutral cued arm. Animals receiving GABA receptor agonists in the
caudal region displayed a bias in the direction of aversion, whereas those undergoing inactivation
of the rostral core displayed an ambivalence similar to controls, with an additional behavioural
difference of augmented chewing. This suggests a rostrocaudal differentiation in valence
processing in the core.
ii
Acknowledgments I would like to thank my supervisor, Dr. Rutsuko Ito, for the opportunities she has given me, for
her guidance, and for always being kind and encouraging. I thank my committee members, Dr.
Suzanne Erb and Dr. Takehara-Nishiuchi, for their feedback and for the interesting questions
they have elicited. I want to thank Dr. Anett Schumacher for all of the skills she has taught me
and for always being cheerfully available to help. Finally I would like to thank my labmate
David Nguyen for all of his intellectual and moral support.
iii
Table of Contents
1 Introduction .......................................................................................................................................... 1
2 Methods ............................................................................................................................................. 12
2.1 Subjects ..................................................................................................................................... 12
2.2 Surgery....................................................................................................................................... 13
2.3 Conditioned Cue Preference Task ........................................................................................ 13
2.4 Training Procedures ................................................................................................................. 14
2.5 Drugs and Infusions ................................................................................................................. 15
2.6 Testing Procedures .................................................................................................................. 15
2.7 Data Analysis ............................................................................................................................ 17
2.8 Histology .................................................................................................................................... 17
3 Results ............................................................................................................................................... 17
3.1 Histology .................................................................................................................................... 17
3.2 Training ...................................................................................................................................... 18
3.3 Conflict test ................................................................................................................................ 18
3.4 Novelty Preference Test .......................................................................................................... 20
4 Discussion ......................................................................................................................................... 20
iv
List of Figures
Figure 1 49
Figure 2 49
Figure 3 50
Figure 4 50
Figure 5 51
v
List of Diagrams Diagram 1 52
Diagram 2 52
Diagram 3 53
Diagram 4 53
Diagram 5 54
vi
1 Running Head: APPROACH-AVOIDANCE PROCESSING 1 Introduction
The most fundamental decisions that an organism must make in order to ensure survival and
reproduction involve the resolution of approach versus avoidance directed toward environmental
signals. Examples of critical behavioural challenges which have persisted over evolutionary
history include foraging for food and water and seeking mates while under the threat of predation
and competition. The main psychological functions that must be performed in service of these
goals include assigning a motivational value, or “valence”, to stimuli based on innate knowledge
and learned experiences, weighting potentially conflicting contingencies, and orchestrating
appropriate behavioural responses in response to a constantly changing internal and external
environment (Cosmides & Tooby, 2013; Tooby & Cosmides, 1990).
In humans, approach and avoidance decisions incorporating ideological values and long-term
goals can be much more complex than those made by other animals, but the brain systems that
evolved to process motivationally significant information are highly conserved across
phylogeny. As such, both rational and sometimes irrational decision-making is performed using
circuitry derived from the heritage of motivated decisions made by our mammalian ancestors
(Levine, 2009; MacLean, 1990). Given that imbalances in the brain’s processing of appetitive
versus aversive information are thought to underlie diverse conditions encompassing addiction,
fear disorders, dysregulated eating, depression and schizophrenia, a deeper understanding of the
neurobiological mechanisms mediating these functions is an overarching goal of many
researchers (Aupperle & Paulus, 2010; Grace, 2010; Robinson & Berridge, 2000).
In mammals, emotional and motivational functions are instantiated in a network of brain
structures including the hypothalamus, neocortical regions, and limbic sites such as the
hippocampus, amygdala and nucleus accumbens (Nieh, Kim, Namburi, & Tye, 2013). The
accumbens is a structure of particular interest given that it is a site of confluence in the
processing of valenced information from many other regions. Mogenson, Jones, and Yim (1980)
corralled evidence and developed the influential idea that the nucleus accumbens is a motor-
limbic interface functionally linking motivation and action. The origin of this idea was attributed
to Graybiel (1976), who noted that the accumbens, by virtue of its position receiving inputs from
limbic structures processing drives and emotions and projecting to basal ganglia structures
2 APPROACH-AVOIDANCE PROCESSING
implicated in the initiation of actions, was ideally situated for this role. The accumbens’ major
dopaminergic innervation from the ventral tegmental area of the midbrain (Moore & Bloom,
1978) was also an important factor in this model, since dopamine had already been implicated in
mediating motivated behaviour (Kelly, Seviour, & Iversen, 1975; Ungerstedt, 1971).
The accumbens and its dopamine innervation have continued to be implicated in reward and
motivation for natural reinforcers such as food and sex, as well as drugs of abuse, which may be
viewed as hijacking the natural reward system (Kelley & Berridge, 2002). The breadth of reward
function subserved by the accumbens is illustrated by studies of food-seeking. The accumbens
has been implicated in mediating the palatability and affective responses to food, the
motivational and approach functions of consumption, as well as in instrumental learning about its
acquisition (Kelley, 2004). Drugs of abuse from diverse categories, including stimulants,
opioids, ethanol and nicotine share the property of triggering dopamine release preferentially in
the nucleus accumbens (Di Chiara, Imperato, & Mulas, 1987; Di Chiara & Imperato, 1988), and
intracranial self-administration studies have demonstrated that animals will work to receive
infusions of dopamine agonists into this structure (Hoebel et al., 1983; Ikemoto, Glazier,
Murphy, & McBride, 1997; Phillips, Robbins, & Everitt, 1994). Most recently, optogenetic
techniques, allowing precise temporal and spatial precision in the activation and inactivation of
neurons, have strengthened support for the role of the nucleus accumbens in mediating
reinforcement (Witten et al., 2011) and in eliciting reward-seeking behaviour in response to
drug-associated cues (Stefanik, Kupchik, Brown, & Kalivas, 2013; Stuber et al., 2011).
The precise role of the accumbens and its dopamine innervation in mediating reward continues to
be debated. For example, researchers have divergently emphasized roles in reinforcement and
hedonia (Wise, 2008), learning associations between stimuli or behaviours and reward (Cardinal
& Everitt, 2004; Day & Carelli, 2007), reward prediction error processing (Schultz, 1998), the
attribution of incentive salience or desirability to reward cues (Berridge & Robinson, 1998;
Berridge, 2007), and in the energization of behaviour toward a given goal (Roitman, Stuber,
Phillips, Wightman, & Carelli, 2004; Salamone, Correa, Mingote, & Weber, 2003). Some of the
debate may originate in a neglect to consider specific localization of function and the role of
neurotransmitters beyond dopamine within the accumbens (Pennartz, Groenewegen, & Lopes da
Silva, 1994). That is, the accumbens is likely to execute myriad functionally and anatomically
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3 APPROACH-AVOIDANCE PROCESSING
distinguishable processes in the service of maximizing adaptive behaviour, given the attendant
computational complexity (Berridge, 2012; Zhang et al., 2009).
The abundance of studies focusing on the accumbens’ role in appetitive behaviour may have also
overshadowed evidence that it is additionally implicated in mediating aversive states; however,
there is an increasing emphasis on viewing this structure as a site of integration of both positively
and negatively valenced information (Carlezon & Thomas, 2009; Levita et al., 2009;
McCutcheon et al., 2012). Functional magnetic resonance imaging studies in humans have
demonstrated that the accumbens undergoes increased activation during exposure to physically
noxious stimuli and cues associated with disgust or fear, as well as in anticipation of aversive
stimuli and the prospect of both gains and losses (Becerra, Breiter, Wise, Gonzalez, & Borsook,
2001; Cooper & Knutson, 2007; Jensen et al., 2003; Klucken et al., 2012). The firing patterns of
cells within the accumbens have been found to be innately tuned to aversive as well as appetitive
stimuli, to develop predictive responses to them, and to be associated with aversive behavioural
output (Roitman, Wheeler, & Carelli, 2005).
Electrophysiological studies have also found that dopamine neurons projecting to the lateral
accumbens shell encode both rewarding and aversive stimuli during primary experience
(Lammel, Ion, Roeper, & Malenka, 2011), and some dopaminergic neurons have been found to
increase their firing rates in response to conditioned and unconditioned aversive stimuli
(Guarraci & Kapp, 1999; Horvitz, 2000). Microdialysis studies have further shown that aversive
or stressful experiences and conditioned aversive stimuli can result in dopamine release in the
accumbens (Salamone, 1994; Young, 2004). Dopamine has been posited to be necessary for
learned avoidance, fear and Pavlovian aversive conditioning (Levita, Dalley, & Robbins, 2002;
Parkinson, Robbins, & Everitt, 1999; Oleson & Cheer, 2013; Zweifel et al., 2011) as well as to
mediate defensive behaviours (Blackburn, Pfaus, & Phillips, 1992). Beyond the effects of
dopaminergic inputs, it has been hypothesized that the accumbens may represent affective state
along a continuum which can be modulated through specific neurotransmitter signatures
incorporating acetylcholine and endogenous opioids (Umberg, Pothos, & Emmanuel, 2011). For
example, acetylcholine may have an important role in mediating aversion, as suggested by its
release in response to satiation, conditioned taste aversion and aversive brain stimulation
(Hoebel, Avena, & Rada, 2007). Selective κ-opioid receptor agonists mimicking the endogenous
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4 APPROACH-AVOIDANCE PROCESSING
ligand dynorphin also produce conditioned place aversions and elicit anhedonic and dysphoric
states in animal models of depression (Bals-Kubik, Ableitner, Herz, & Shippenberg, 1993;
Mague et al., 2003).
The capacity for traditionally reward-associated circuitry to mediate aversive states is also
suggested by the fact that exposure to drugs of abuse can cause neuroadaptations resulting in
depressive symptoms such as anhedonia and diminished motivation. While these effects of drug
usage may be viewed as homeostatic responses to supraphysiogical neurotransmitter levels, the
underlying circuitry appears to be naturally prepared to mediate aversive states. That is, aversive
states such as occur during drug withdrawal are suggested to result not only from a rebound
diminishment of reward system function, but due to the active recruitment of an “antireward”
system associated with stress and anxiety, and mediated by neurotransmitters such as
corticotropin releasing factor, norepinephrine and dynorphin, all of which can act upon the
nucleus accumbens (Koob & Le Moal, 2008).
The accumbens is densely innervated by the amygdala, a structure which has traditionally been
implicated in fear (Ledoux, 1995) but is now thought to signal the salience of both positive and
negative stimuli (Breiter et al., 1996; Hamman, Ely, & Hoffman, 2002; Morrison & Salzman,
2010). It is also innervated by other regions which have been found to process both rewarding
and aversive information, including the orbitofrontal cortex, cingulate cortex and the insula
(Hayes & Northoff, 2011; Vogt, 2005). Within subregions of the prefrontal cortex, there appears
to be regionally distinct processing of rewards and punishments (Monosov, Ilya, Hikosaka, &
Okihide, 2012). Other input and output structures of the accumbens have also been found to be
segregated in terms of response to positively or negatively valenced information. For example, a
contrast was found between dorsal and ventrally located dopamine neurons in the ventral
tegmental area, such that they responded reciprocally to noxious footshock stimulation
(Brischoux, Chakraborty, Brierly, & Ungless, 2009). Thus it appears that a reiterative
representation of both appetitive and aversive information may occur over multiple network
sites, including within the accumbens. The incorporation of bivalenced information in the
accumbens coheres with its postulated role as an arbitrator of behavioural output, whereby
multiple potentially conflicting outcomes must be considered (Humphries & Prescott, 2010). In
this light, human neuroimaging studies have reported accumbens activation to correlate with the
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5 APPROACH-AVOIDANCE PROCESSING
amount of risk involved in decision-making (Kuhnen & Knutson, 2005; Tom, Fox, Trepel, &
Poldrack, 2007).
Given the heterogeneity of functions which have been attributed to the accumbens and the
evidence that other brain structures appear to have dedicated subregions in the processing of
contrasting valence, researchers have increasingly attempted to refine the localization of different
processes and neurochemical characteristics. The nucleus accumbens has been subdivided
morphologically, functionally and histochemically into two major subterritories: a core and a
shell which extends medially, ventrally and laterally around it (Meredith, Baldo, Andrezjewski,
& Kelley, 2008; Voorn, Gerfen, & Groenewegen, 1989). The two subregions differ significantly
in their afferent input and efferent projections. For example, different subcompartments of the
amygdala, hippocampus, and prefrontal cortex project to the shell versus the core. The output of
the core connects extensively to basal ganglia motor output structures including the ventral
pallidum, subthalamic nucleus and substantia nigra, whereas the shell projects preferentially to
subcortical limbic regions including the lateral hypothalamus, ventral tegmental area and
brainstem autonomic centers (Heimer, Zahm, Churchill, Kalivas, & Wohtlmann, 1991; Zahm &
Brog, 1992). Functional magnetic resonance imaging studies have also found distinct patterns of
connectivity with prefrontal cortical and subcortical limbic targets between the core and shell,
along with differentiable activation patterns in response to both rewarding and aversive events
and their predictive cues (Baliki et al., 2013).
The shell in particular has been posited to mediate the primary or unconditioned rewarding
effects of drugs. Supporting this idea, it has been found that drugs and natural reinforcers
preferentially increase dopamine release in the shell (Aragona, Cleaveland, Stuber, Day, &
Carelli, 2008; Ito et al., 2001; Pontieri, Tanda, & Di Chiara, 1995), and animals will self-
administer dopamine agonists and reuptake inhibitors specifically into the shell, as opposed to
the core (Carlezon, Devine, & Wise, 1995; Rodd-Henricks, McKinzie, Li, Murphy, & McBride,
2002). Primary reward functions are closely linked with learning; that is, it is thought that the
primary reinforcing experience, as can be elicited by dopamine in the accumbens shell, is an
integral agent in forming associations between conditioned and unconditioned stimuli (Pavlovian
learning), and in the acquisition of instrumental behaviour (Di Chiara et al., 2004; Gambarana et
al., 2003). The accumbens core, on the other hand, has often been implicated in mediating the
5
6 APPROACH-AVOIDANCE PROCESSING
motivation or elicitation of instrumental and approach behaviours in response to previously
associated cues (Ghitza, Fabbricatore, Prokopenko, & West, 2004; Ito, Robbins, & Everitt, 2004;
Parkinson, Willoughby, Robbins, & Everitt, 2000; Sellings & Clarke, 2003). These potentially
dissociable functions may explain the results of a study indicating that dopamine release in the
shell was necessary for the acquisition, but not the expression of, conditioned place preference
(Fenu, Spina, Rivas, Longoni, & Di Chiara, 2006).
Another dimension on which the functions of the core and shell have been contrasted is that of
processing discrete cue versus spatial or contextual information. Lesions to the shell region have
been found to impair the acquisition of spatially-sensitive place preference, whereas lesions of
the core have been found to impair the acquisition of conditioning to a discrete cue, behaviours
which may depend upon their respective connections to the hippocampus and amygdala (Ito,
Robbins, Pennartz, & Everitt, 2008). The accumbens core has also been implicated in cue-
induced reinstatement of heroin-seeking, while the shell has been implicated in context-induced
reinstatement (Bossert, Poles, Wihbey, Koya, & Shaham, 2007), and analogous results were
found in cue versus context-elicited ethanol seeking (Chaudhri, Sahuque, Schairer, & Janak,
2010).
Beyond the delineation of core and shell, there is increasing evidence of structural and functional
differentiation arranged topographically within these boundaries. A series of studies has
suggested, for example, that within the shell there is a rostrocaudal gradient in the processing of
valence; that is, it has been found that disruption of normal activity in the rostral shell leads to
increases in appetitive behavior, whereas disruption in the caudal shell leads to aversively biased
behavior. This line of inquiry originated in an attempt to replicate and extend upon findings from
the lab of Ann Kelley, where it was found that local hyperpolarizations in the accumbens shell
using either an AMPA glutamate receptor antagonist or a GABAA receptor agonist resulted in
large increases in food consumption (Basso & Kelley, 1999; Stratford & Kelley, 1998). Reynolds
and Berridge (2001) sought to confirm these findings, and further to assay regions more caudal
than had previously been probed. In fact, as noted by Richard, Castro, DiFeliceantonio, Robinson
and Berridge (2013), most localized injection studies before the year 2000 were directed
primarily to the rostral half of the accumbens, a phenomenon they term “caudal neglect”. A
reason the authors posited for this oversight is that stereotaxic atlases previously represented the
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7 APPROACH-AVOIDANCE PROCESSING
accumbens shell in a compressed form, such that the entire rostrocaudal distance depicted has
increased by approximately 1 mm from the time of the popular atlas of the 1960s to that
commonly used today (Paxinos & Watson, 2007; Pellegrino & Cushman, 1967). In particular,
the represented distance between the anteroposterior midpoint of the medial shell to the caudal
edge has increased by approximately 0.5 mm in Paxinos and Watson between 1998 to 2007, and
a rostral migration of stereotaxic coordinates is seen in the coronal sections of the successive
atlas editions. As such, locations considered to be posterior in the 1990s are now recognized to
have been only central within the medial shell.
Reynolds and Berridge (2001) thus confirmed that microinjection of the GABAA receptor agonist
muscimol into the rostral to middle regions of the medial shell elicited intense eating, as
previously found. But as they progressively probed more caudal locations, they discovered that
the manipulation failed to generate feeding behavior, and at the most caudal regions, food intake
was in fact suppressed. Moreover, they observed an elicitation of intense aversive behaviour in
the form of anti-predator reactions such as defensive treading and burying. These behaviours are
seen in wild rodents when they eject debris or dirt toward a predator (Coss & Owings, 1978; De
Boer & Koolhaas, 2003) and in laboratory paradigms in response to shock sources or predator
odors (Treit, Pinel, & Fibiger, 1981). The same rostrocaudal pattern of feeding and fear
behaviour was found to be elicited through localized inhibition using the AMPA glutamate
antagonist DNQX (Faure et al., 2008; Reynolds & Berridge, 2003). Caudally elicited fear
behaviours were further documented to be more diverse than the specific action pattern of
defensive treading: animals were found to respond to experimenters’ approach and touch with
distress vocalizations, escape attempts and defensive biting (Reynolds & Berridge 2002, 2003).
In addition to the aforementioned motivated behaviours, rostrocaudal gradients were also found
in primary hedonic experiences modulated by GABA receptor (GABAR) inhibition in the shell;
that is, in “liking” or “disliking” taste reactions (Faure, Richard, & Berridge, 2010; Reynolds &
Berridge 2002). Animals given a bittersweet solution of sucrose and quinine displayed more
positively valenced reactions, such as lip licking, when infused with muscimol in the rostral
shell, and increasingly negative hedonic reactions, such as mouth gaping, when infusions were
more caudally administered. However, unlike in the assays of food consumption or defensive
behaviours, this same pattern was not elicited through inhibition via glutamate antagonism,
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8 APPROACH-AVOIDANCE PROCESSING
whereby hedonic taste reactions were unaffected (Faure et al., 2010). In addition to amino acid
manipulations, a mapping using mu opioid receptor agonism has localized a hedonic
enhancement site to the rostral half of the medial shell (Pecina & Berridge, 2005).
Further evidence of a rostrocaudal gradient in the mediation of valence was found using an
additional behavioural measure. The conditioned place preference/avoidance paradigm is a
traditional measure of rewarding or aversive properties of natural or pharmacological stimuli,
wherein an increase in time spent in an environment previously paired with the stimulus is taken
to indicate its reinforcing properties, and decreased time spent therein is thought to index
negatively reinforcing properties (Tzschentke, 2007). The choice made during exploration may
then be interpreted in terms of the expression of conditioned approach versus avoidance
motivation (Huston, de Souza Silva, Topic, & Muller, 2013). Reynolds and Berridge (2002)
found that GABAR agonism via muscimol microinjections into the accumbens shell resulted in
conditioned place preference at most rostral sites, but place avoidance at most caudal sites.
However, analogously to the contrast observed in hedonic taste reaction, glutamate antagonism
in the rostral shell via DNQX injections failed to enhance the positively valenced behaviour and
in fact established week place avoidance A rostrocaudal gradient was still however apparent, in
that more caudal injections established strong conditioned place avoidance (Reynolds &
Berridge, 2003). This diversity of behaviours demonstrating a rostrocaudal gradient in valence
suggested that the manipulations were not merely eliciting specific action patterns, but were
more generally capable of evoking a central motivational state of reward or aversion (Kelley,
Baldo, Pratt, & Will, 2005).
It should be noted that the sites of enhancement of appetitive behaviours do not all perfectly
overlap between measures; thus in more central locations along a rostrocaudal gradient, it was
possible to elicit strongly augmented feeding concurrently with place aversion and aversive
hedonic taste reactivity (Reynolds & Berridge, 2002). Moreover, the regionally mediated
valence was found not to be absolutely determined; manipulations of environmental context
could to some extent retune the bias of behaviour by altering the topographically valenced
boundaries. For example, Reynolds and Berridge (2008) found that the rostral 25% region
wherein glutamate disruptions were previously shown to generate appetitive behaviour could be
expanded caudally to fill up to 90% of the shell if testing occurred in a preferred home
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environment, whereas caudal fear generating zones could similarly be expanded if testing
occurred in a stressful environment. This serves to highlight the role of the accumbens not only
in conditioned and unconditioned aversive or appetitive behaviour, but in the integration of
information about the animal’s current situation in order to select the appropriate response at the
time of behavioural expression (Humphries & Prescott, 2010).
Approximately 90-95% of neurons in the NAc are medium-sized spiny neurons, a class of
GABAergic neurons which project inhibitory signals to downstream sites including the lateral
hypothalamus, ventral pallidum and mesencephalic dopaminergic regions (Chang & Kitai,
1985). These neurons receive extensive glutamatergic input from the prefrontal cortex,
hypothalamus, basolateral amygdala and hippocampus (Groenewegen, Wright, & Beijer, 1996),
and GABAergic input from local fast-spiking interneurons as well as subcortical structures such
as the ventral pallidum and ventral tegmental area (Taverna, Dongen, Groenewegen, & Pennartz,
2004). As such, both GABAR agonists and glutamate antagonists are expected to result in local
hyperpolarization and a reduction in action potential firing, and thereby provide a disinhibition to
efferent sites (Faure et al., 2010; Koos, Tepper, & Wilson, 2004). Where differences have been
found between the effects of GABAR agonism and glutamate antagonism (Faure et al., 2010),
the authors suggest that there are differences in mechanism which may result in a stronger
influence of GABAergic activation on the resultant output of the accumbens. For example,
muscimol acts on GABAA receptors located on somata and proximal dendrites, whereas AMPA
receptors are more likely to be found on distant spines and require interaction with endogenous
dopamine at the same site (Chen, Veenman, Knopp, Yan, & Medina, 1998). The observed
differences may also reflect the relative influence of the differentiated GABA and glutamate
input structures relevant to a given behaviour.
Thus one interpretation for the increased consummatory behaviour observed in response to
rostral accumbens manipulations is the release from inhibition of a site known to evoke feeding,
in particular within the hypothalamus. Kelley, Baldo, Pratt, and Will (2005) posit that the
inhibition of direct GABAergic projections arising exclusively within the medial shell (Heimer,
Zahm, Churchill, Kalivas, & Wohltmann, 1991) results in a release of motor feeding patterns that
are instantiated in lateral hypothalamic circuitry. Other functional contrasts observed along the
rostrocaudal axis may also be attributed to differentiated patterns of accumbens projection
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neurons, as there is increasing evidence that the accumbens should be viewed not in terms of a
monolithic function and output, but instead as a collection of distinguishable neuronal ensembles
(Pennartz, Groenewegen, & Lopes da Silva, 1994).
Although the precise nature of the relationship between connectivity and functionality remains to
be elucidated, many distinctive rostrocaudal patterns of afferent and efferent input are already
known. For example, the ventral region of the subiculum projects predominantly to the
caudomedial region of the accumbens, whereas progressively more dorsal regions of the
subiculum project to successively more lateral and rostral areas of the accumbens (Brog,
Salyapongse, Deutch, & Zahm, 1993). The mediodorsal nucleus of the thalamus may also
preferentially target the rostral half of the accumbens (Phillipson & Griffiths, 1985).
Additionally, within the accumbens, afferent projections from specific hippocampal regions
converge together with inputs from particular sub-nuclei of the basal amygdaloid complex in a
site-specific manner: In the rostral accumbens there is a convergence of inputs from the
intermediate septotemporal hippocampus and the intermediate rostrocaudal amygdala, whereas
in the caudal accumbens, there is a convergence between projections from the ventral
hippocampus and the caudal basal amygdaloid complex (Groenewegen, Wright, Beijer, &
Voorn, 1999).
Regional differences in histochemistry may also underlie the observed functional differences.
Differential regional patterns within the accumbens have been found in the expression of
calcium-binding protein, enkephalin and dynorphin in the rostral versus caudal core (Berendse,
Groenewegen, & Lohman, 1992; Voorn, Gerfen, & Groenewegen, 1989). These variations may
in turn reflect differential connectivity; for example, calbindin-poor regions receive deep layer V
cortical input and project to non-dopaminergic cells, whereas neurons in calbindin rich regions
receive superficial layer V cortical input and project to non-dopaminergic cells (Berendse et al.,
1992; Humphies & Prescott, 2010). Rostrocaudal differentiations have also been found in
substance P immunoreactivity and acetylcholinesterase activity (Jongen-Relo et al., 1994). In a
study using fast-scan cyclic voltammetry and pharmacological manipulations, it was found that
norepinephrine signaling was restricted to the caudal accumbens (Park, Aragona, Kile, Carelli, &
Whiteman, 2010). Rostrocaudal gradients in both the shell and core were found in the effects of
dopamine depletion on enkephalin, dynorphin and substance P mRNA levels (Voorn, Docter,
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Jongen-Relo, & Jonker, 1994), suggesting to the authors that the rostral and caudal regions of the
accumbens are likely to be involved in different functions, particularly in relation to interactions
with dopamine. Moreover, a decrease in the effect of D2 receptor activation on acetylcholine
release was also found along the rostraudal axis (Henselmans & Stoof, 1991). Finally, a
rostrocaudal gradient in both dopamine D1 and D2 receptors has been measured, such that the
density of both types has been found to be greater in rostral than in caudal regions (Richfield,
Young, & Penney, 1987). The gradient appears to be more gradual for D2 receptors, and results
in a 50% lower quantity in caudal as compared with rostral regions, whereas D1 density is
largely homogenous until the most caudal regions, where they appear to be 30% lower in density
than in anterior regions (Bardo & Hammer, 1991). The gradient was found to be independent of
the core and shell dichotomy (Voorn, Jongen-Relo, & Jonker, 1994).
Since many of the aforementioned gradients have been observed in the accumbens core in
addition to the shell, analogous functional differences may also be found in the core region,. An
example of a potential functional gradient in the core derives from research in fear conditioning.
In considering possible reasons underlying discrepant results in studies measuring dopamine
release in the accumbens core during exposure to aversively conditioned stimuli, Levita, Dalley,
and Robbins (2002) noted that there was variance between research labs in the placement of
probes along the rostrocaudal axis. The authors pointed out that in a study finding evidence of
increased dopamine release, probe placements were positioned in the rostral region (Wilkinson et
al., 1998), whereas in their own study, using placements in more caudal regions, the authors
found no evidence of enhanced release. In studies having more variability in probe placement,
the resulting neurochemical data in turn tended to have considerably high variability (Murphy,
Pezze, Feldon, & Heidbreder, 2000; Pezze, Heidbreder, Feldon, & Murphy, 2001). The authors
suggest that cue conditioned dopamine release may be a regionally specific phenomenon, and
advised that in general it may be important to consider anatomical heterogeneity in the
accumbens, in particular along the rostrocaudal gradient, in interpreting research findings.
The accumbens core has been less fully characterized in terms of a potential gradient in valence
processing as compared with the shell. In one study by Reynolds & Berridge (2003), the authors
failed to find a rostrocaudal gradient in the accumbens core in fear or feeding behaviours as
elicited by glutamate antagonist microinfusions. However, the behaviours measured constituted
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only innate unconditioned reactions, as opposed to measures of motivation in relation to
conditioned cues. The effects of localized GABA receptor manipulations within the accumbens
core have also not yet been assessed. Given the evidence for a particular role of the nucleus
accumbens core in the elicitation of motivated behaviour in response to conditioned cues (Ito,
Robbins, & Everitt, 2004; Stefanik, Kupchik, Brown, & Kalivas, 2013; Stuber et al., 2011), in
the current study we sought to determine whether inactivations in the core might yield
differential effects on cue-triggered Pavlovian approach behaviour depending on the rostrocaudal
site. In particular, an assessment was made of a rostral as compared with a historically neglected
caudal site. The study employed a modified conditioned place-preference paradigm using
discrete cues which were associated with the presence of appetitive and aversive outcomes.
GABA receptor (GABAR) agonism via microinfusion in the accumbens was used to assess the
potential biasing effects of localized inactivation on an approach/avoidance exploratory decision
in the face of signals indicating both appetitive and aversive outcomes. It was hypothesized that
animals receiving rostral infusions of the GABAR agonist would display a bias toward approach
in the expression of conditioned approach/avoidance, as evidenced by an increased amount of
time spent in the conflicting cue arm as compared with saline control animals, and that animals
receiving infusions in caudal regions would display a bias toward aversion in the face of the
conflicting cues, as evidenced by decreased time spent in the conflicting cue arm.
2 Methods
2.1 Subjects
Experimental procedures were performed using male Long-Evans rats (Charles River
Laboratories) weighing between 350 and 400g at the time of surgery. They were housed in pairs
under a 12 hour light/dark cycle, with lights turning off at 7:00 pm. Experiments occurred during
the light phase of the cycle. Water was available ad libitum, but beginning 2 days prior to
training, food was restricted sufficiently to reduce and then maintain their body weight at 85% of
their baseline value. All procedures were performed in accordance with the guidelines of the
Canadian Council of Animal Care.
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2.2 Surgery
Animals were anaesthetized using 3-4% isofluorane and placed in a frame for stereotaxic
surgery. A 26-gauge stainless steel bilateral guide cannula (Plastics One) was implanted into one
of the following coordinates (in mm from bregma): rostral accumbens core (AP = + 1.7, ML = ±
1.5, DV = -5.6) or caudal accumbens core (AP = +0.7, ML = ± 1.5, DV = -5.7). At the time of
infusions, injector tips extended by 1 mm below the guide cannulae, and thus the final targeted
location was at 1mm ventral to the above coordinates. The guide cannulae were affixed to the
skull using dental cement and jeweler’s screws. Stainless steel obdurators were inserted into the
guide cannulae in order to maintain patency. Rats received injections of 5mg/kg Anafen (Merial
Canada Inc.) 20 minutes prior to awakening in order to minimize pain. Animals underwent a
minimum recovery period of 7 days in their homes cages before beginning experimental training.
2.3 Conditioned Cue Preference Task
Radial Maze Apparatus. Behavioral training and testing was conducted using a six-arm radial
maze apparatus (Med Associates). The six arms converged at a hexagonal hub where automated
steel guillotine doors controlled access into each arm (45.7 cm length, 9 cm width, 16.5 cm
height). The arms were enclosed with Plexiglas walls, a removable lid and a steel grid floor
which was connected to a footshock-generating device (Med Associates). A receding well was
located at the end of each arm, which was connected to input tubing and a syringe for the
delivery of sucrose solution. The apparatus was covered with red cellophane in order to obscure
extra-maze stimuli. Med PC IV software (Med Associates) was used to control the timing of
maze door opening. A ceiling-mounted camera was positioned above the apparatus to allow for
monitoring and recording of test sessions. Sessions occurred under illuminated conditions in
order to ensure cue visibility.
Discrete Cues. During training and test trials, wooden rectangular inserts measuring 45 x 2.5 cm
and covered with either gray duct-tape, blue denim cloth material or exposed wooden finish were
placed along both bottom lengths of maze arms and affixed using Velcro. The inserts were thus
discriminable in terms of texture, colour and reflective properties. The inserts become cues
predictive of either sucrose availability, footshock administration, or neutral conditions (no
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scheduled events) in a given arm during the training sessions. The valence of cues for a given rat
was determined following the unvalenced cue habituation session (described below), whereby
any innate preference for a cue was counterbalanced by assigning it to the opposite valence
during conditioning.
2.4 Training Procedures
Habituation (day 1). Two habituation sessions were conducted on the first day of the
experiment. No unconditioned aversive or appetitive stimuli were presented in either session.
During the first habituation session, no cues were inserted into the arms. Rats were placed
individually in the central hub to begin the session with all doors closed. After one minute, three
doors were raised in order to allow free exploration of the identical arms and the hub for a period
of 5 minutes. After this time, all doors were lowered and the animal was removed from the
apparatus. During the second habituation session, the cues were inserted into 3 separate arms
and the same sequence of events occurred as above. The amount of time spent exploring each
arm was measured and used to determine the valence of each cue for a given rat, as explained
above. Following the apparatus habituation session, rats were given access to sucrose solution in
their home cages for 5 minutes in order to habituate to its consumption.
Training (days 2-10). Training sessions were conducted once daily over a period of 9
consecutive days. The appetitive, aversive, and neutral cues were placed in randomized arms
prior to each trial, varied between subjects within a session, and within subjects between
sessions, in order to minimize any conditioning to extraneous intra-maze cues or odors. A
syringe for sucrose administration was connected via polyethylene tubing to the well in the arm
containing the appetitively valenced cue. The flooring in the arm containing the aversively
valenced cue was connected to the footshock generator. At the start of each session, a rat was
confined in the central hub. After 30 seconds, an initial door was elevated to allow access to one
arm. Upon entry of the animal, the door was lowered to restrict the rat to that arm for a period of
120 seconds. During this time, the animal was administered either the unconditioned appetitive,
aversive, or no stimulus, depending on the intended valence of the cue contained within that arm.
The appetitive stimulus was administered as an infusion of 2.0 ml of sucrose delivered 4 times at
an interval of approximately 30 seconds. The aversive stimulus was a footshock lasting 0.5
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seconds of approximately 0.25 mA, as calibrated to the level at which the animal demonstrated a
startle response. The footshocks were administered at approximately 30 second intervals. At the
end of the period in each arm, the door was opened to allow reentry of the animal into the central
hub, whereupon it was confined for 30 seconds until a second arm was opened. The same
procedure then followed for the arms of the other 2 valences, and the animal was subsequently
removed from the apparatus to terminate the session. The order of entry into arms of each
valence was varied across trials. The arms were cleaned with 70% ethanol in water between
animals and sessions. The maze was rotated by varying degrees at the end of each testing day in
order to prevent any conditioning to extra-maze spatial or contextual cues. (See Diagram 1 for a
visual depiction of the apparatus).
2.5 Drugs and Infusions
For three days prior to infusion sessions, animals were habituated to gentle hand restraint in the
manner and environment in which infusions were to be administered. On the day before the first
drug session, all animals received an infusion of the saline vehicle, in order to minimize the
effects of subsequent infusions and to further habituate the animals to the procedure. On
infusion days, animals received 0.3µl bilateral intracerebral microinjections of a solution
containing a mixture of the GABAA receptor agonist muscimol and the GABAB receptor agonist
baclofen, (75 ng of each drug per infusion) (Sigma-Aldrich) dissolved in physiological saline, or
the saline vehicle only. The drug was infused via 33 gauge microinjectors projecting 1 mm
below the indwelling guide cannulae using an infusion pump (Harvard Apparatus) mounted with
5µl Hamilton syringes. The infusion occurred at a rate of 0.3µl/46 sec, and the injector was left
in place for an additional 1 min in order to ensure complete diffusion of the drug from the
injector tip. Approximately 10-15 minutes following the end of each infusion, behavioural
testing occurred in the conflict task (described below).
2.6 Testing Procedures
Acquisition of Conditioned Cue Preference. In order to assess the acquisition of conditioned
cue preference, testing sessions were conducted under drug-free conditions after training day 8.
Testing sessions followed the protocol used during the second habituation session. The rat was
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permitted free access to three arms which each contained one of the three sets of valenced cues,
but no unconditioned stimuli will be presented. The amount of time spent exploring each arm
was measured and recorded via video monitoring. A rat was determined to have entered a given
arm when both its front and hind paws crossed the door threshold, and likewise to have exited
the arm when all of its paws had entered the central hub. Conditioned cue preference tests were
followed by an additional session of training on day 9.
Conflict Test for the Expression of Approach vs. Avoidance. A final test session was
conducted on the 10th
day. The aversively conditioned cue was superimposed with the appetitive
cue within a single arm. A second arm contained the neutral cue. The animal was placed inside
the central hub at the start of the session with all doors closed. After a 1-minute period, two
doors were raised, allowing access to the conflicting-cue and neutral arms. The rat was allowed
to explore both arms in addition to the central hub for a period of 5 minutes. No unconditioned
stimuli were administered. The amount of time spent exploring each arm was measured and
recorded via video monitoring. (See Diagram 2 for a visual depiction of the apparatus).
Novelty Preference Test. Rats performed a novelty preference task in order to determine
whether the drug manipulation might result in an altered preference for novel visual cues which
could explain any difference observed in exploration of the superimposed cues during the
conflict test, given that it was a relatively novel configuration. At the beginning of the exposure
phase, animals were introduced to the central hub of the radial maze for a thirty second
habituation period. Doors to two arms were subsequently opened, and for 10 min the rats were
free to explore the arms, which were characterized by distinct visual patterns on their walls
(black and white circles, diagonal, or horizontal lines) (See Diagram 3). The animals were then
removed from the apparatus for an interval period of 10 minutes. During the testing phase,
animals were returned to the apparatus for 5 min, whereupon three arms will be open, two of
which contained the previously observed cues and one of which contained a novel pattern. The
average time spent exploring the familiar arms was measured and compared with that spent
exploring the novel arm (See Diagram 4).
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2.7 Data Analysis
In order to assess motivational bias during the conflict test, a within-subjects ANOVA was
performed with the factors of drug condition (saline vs. baclofen/muscimol) and location of the
microinfusion (rostral accumbens core or caudal accumbens core). The dependent measure was
the amount of time spent in the conflict arm versus the time spent in the neutral arm. In order to
assess animals’ learning of the valenced cue associations during the training period, a within
subjects ANOVA was conducted for the dependent measure of time spent in each arm
(appetitive, neutral, aversive). The factors of future drug condition (saline vs.
baclofen/muscimol) and cannula location (rostral core vs. caudal core) were evaluated to
determine whether there were any preexisting group differences in learning.
2.8 Histology
After completion of the behavioural testing, animals were sacrificed using 1200mg/kg chloral
hydrate (Sigma-Aldrich) and perfused intracardially with 100 ml saline, followed by 100 ml of
4% paraformaldehyde (PFA) in phosphate buffered saline. Brains were then removed and stored
in PFA before being transferred to a sucrose cryoprotectant. Coronal slices of 50µm diameter
were cut with a freezing microtome, and then stained with cresyl violet for viewing under a
microscope in order to verify the placement of cannulae. Only animals having the correct
targeted cannula placements were included in the data analysis.
3 Results
3.1 Histology
Brain slices were verified for the placement of injector tips in the nucleus accumbens core, with
reference to the stereotaxic atlas of the rat brain of Paxinos and Watson (1997). Data from 11
animals was excluded from statistical analyses due to incorrect cannula placement (n = 6), loss of
the cannula during training (n = 5) and infection (n = 1). The final group numbers were as
follows: caudal core inactivation, n = 7; caudal core saline, n = 9; rostral core inactivation, n =
8; rostral core saline, n = 11. (See Diagram 5 for cannula placements).
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3.2 Training
A three-way within subjects ANOVA was conducted on exploration time in the three arms
during a final preference test at the end of training in order to determine whether the animals had
learned to associate the valenced cues with the aversive and appetitive outcomes. Degrees of
freedom were adjusted using a Huynh-Feldt correction as Mauchly’s Test indicated a violation of
sphericity. A significant main effect of arm was found, F(1.72, 51.51) = 27.35, p < .001. Paired
samples t-tests revealed that animals spent a greater amount of time in the appetitive vs. the
neutral cued arm, t(33) = 2.46 , p = .019, and less time in the aversive as compared with the
neutral arm, t(33) = 6.39, p = < .001 (Figure 1). There were no significant main effects found for
cannula location, F(1, 30) = .72 , p = .40 or drug condition, F(1, 30 ) = .257, p = .62, nor were
there any significant interactions, indicating that the groups did not exhibit any pre-existing
differences in learning after training (Figure 2).
3.3 Conflict test
A three-way within subjects ANOVA was conducted to compare the amount of time spent in the
neutral vs. conflict arm for the two different drug conditions (GABAR agonist inactivation and
saline) and two different cannula placement locations (rostral vs. caudal accumbens core). The
results indicated a main effect of arm valence on exploration time, with animals overall spending
a greater amount of time in the neutral as compared with the conflict arm, F(1, 31) = 6.91, p =
.013. Significant main effects were also found for drug condition, F (1, 31) = 13.49, p = .00 and
cannula location, F(1, 31) = 15.23, p = .00. Significant two-way interactions were found between
arm and drug condition, F(1, 31) = 17.22, p = .00 and drug condition and cannula placement,
F(1, 31) = 9.20, p = .005, and a three-way interaction was observed between arm, drug condition
and cannula placement, F(1, 31) = 8.87, p = .006.
Tests of simple effects were conducted in order to specify the differences between conditions as
observed in the significant interactions. Among animals having cannula placements in the caudal
core it was found that saline animals did not differ significantly in the time spent exploring the
conflict versus neutral arms, F(1, 14) = 1.91, p = .19, whereas the inactivated animals spent
significantly less time in the conflict as opposed to the neutral arm, F(1, 14) = 15.82, p = .001
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(Figure 3). Among animals having cannula placements in the rostral core, the saline group again
did not differ in time spent exploring the conflict versus neutral arms, F(1, 17) = .053, p = .82.
The inactivation group spent more time in the neutral as opposed to the conflict arm, however
the difference was not statistically significant, F(1, 17) = 2.99 , p = .10 (Figure 4). Thus the
saline animals in both cannula placement groups displayed ambivalence in their approach
behaviour toward the arm containing both appetitive and aversive cues, whereas animals
receiving GABAR agonists in the caudal region of the core displayed an increased aversion
toward the arm containing the mixed valence cues. Animals who underwent GABAR agonist
inactivation in the rostral region of the core did not demonstrate the same increased aversion to
the conflict arm as the caudal group, and instead displayed an ambivalence between the arms.
A separate ANOVA was conducted to assess whether total exploration time outside of the central
hub differed based on cannula location and drug condition. Significant main effects were found
for both cannula location, F(1, 31) = 15.23, p = .00 and drug condition, F(1,31) = 13.49, p = .001
and a significant interaction was found between drug condition and cannula location, F(1, 31) =
9.20, p = .005. Tests of simple effects revealed that among saline animals, total exploration time
did not differ between animals in the rostral and caudal location groups, F(1, 31) = .441, p = .51,
whereas among the inactivation animals, those having rostral cannula placements displayed
significantly lower total exploration times than those having caudal cannula placements, F(1,31)
= 21.09, p = .00. Among animals having caudal cannula placements, total exploration time did
not differ significantly between saline and inactivation animals, F(1,31) = .190, p = .67, whereas
among animals having rostral cannula placements, the animals undergoing inactivation displayed
significantly reduced total exploration times, F(1, 31) = 24.46, p = .00.
An observation of the behaviour of the animals during the conflict test suggested a qualitative
difference contributing to the decrement in total exploration time in the rostral core inactivated
animals. It was observed that these animals spent a significant amount of time performing
unusual chewing behaviour. Many of the animals did not exit the central hub, and instead spent
the duration of the testing period performing chewing motions with either no substrate in their
mouths or directed toward substrates not seen in the control animals, such the edge of the
apparatus or their own body parts. Among animals who departed the central hub, most of the
animals made only one arm entry in total, and spent the majority of time in one place chewing on
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a cue, edge of apparatus, or body part. This chewing time was subtracted from the arm
exploration times used in the analysis. Chewing time in the central hub was not quantified due to
visibility limitations.
3.4 Novelty Preference Test
A test of novelty preference was conducted in animals with caudal core cannula placements in
order to determine whether inactivation resulted in an altered exploratory bias for novel visual
cues. Paired sample t-tests were conducted to compare the average time spent in the familiar vs.
the novel arms. Saline animals spent a greater amount of time in the novel arm, t(7) = 2.72 , p =
.030, indicating a preference for the novel spatial environment. While animals undergoing
inactivation in the caudal core spent a greater amount of time in the novel as opposed to familiar
arm, the difference was not statistically significant due to a high level of variability, t(5) = .36, p
= .73 (Figure 5). The data collected for animals with rostral core cannula placements was
insufficient for analysis, as the majority of the animals did not complete all required phases of
the experiment, such as by failing to explore all arms during the exposure phase, or failing to exit
the central hub during testing.
4 Discussion
The current results provide evidence for a topographical differentiation in function along the
rostrocaudal axis of the nucleus accumbens core for the processing of valenced cues in the
motivation of approach and avoidance. Inactivation of the caudal accumbens core via GABAR
agonism resulted in a bias toward aversion as compared with normal controls, whereas
inactivation of the rostral core resulted in an ambivalence similar to that observed in control
animals. An additional behavioural difference was observed in rostrally inactivated animals in
that they displayed a reduction in exploratory activity and a significant augmentation of chewing
behaviour.
Previous experiments involving pharmacological manipulations of the nucleus accumbens shell
found opposite effects of inactivation in the caudal vs. rostral regions in the elicitation of
negatively vs. positively valenced consummatory and defensive behaviours (Faure, Reynolds,
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Richards & Berridge, 2008; Reynolds & Berridge, 2001). A similar assessment in the nucleus
accumbens core did not demonstrate any difference in these behaviours along a rostrocaudal
gradient, suggesting to the authors that the core may not observe the same regional bivalent
gradation in valence processing (Reynolds & Berridge (2003). However, these inactivations were
performed using a glutamate antagonist, as opposed to via a GABAR agonist as employed in the
current study. Additionally, the behaviours previously measured constituted only innate
reactions to unconditioned stimuli. Given the evidence for a particular role of the nucleus
accumbens core in the elicitation of motivated behaviour in response to conditioned cues
(Stefanik, Kupchik, Brown, & Kalivas, 2013; Stuber et al., 2011), we sought to determine
whether inactivations in the core might yield differential effects on cue-triggered Pavlovian
approach behaviour depending on the rostrocaudal site. The finding that caudal inactivation
caused greater avoidance than that observed under rostral inactivation may be analogous to the
results of investigations in the accumbens shell. That is, in both cases there is evidence for a
rostrocaudal gradient in the processing of valence, with disruption in activity in more caudal
regions resulting in greater aversive behaviour.
The augmentation in avoidance behaviour observed during the conflict test in animals
undergoing GABAR agonsim in the caudal core suggests that this region may have a particular
role in motivating avoidance behaviour in response to aversively predictive cues. While
GABAR agonism is considered to result in localized neural inactivation, this may in effect
activate a functional output pathway. That is, given that the output neurons of the accumbens are
GABAergic in nature (Chang & Kitai, 1985), a reduction in activity of these inhibitory output
neurons may in turn result in greater activation of a downstream structure effecting the avoidance
behaviour. In light of the postulated function of the nucleus accumbens as a site of integration of
information and a selector of appropriate behaviour (Humphries & Prescott, 2010), it may be the
case that the caudal core has the capacity to either elicit or inhibit aversive behaviour, according
to current circumstances as informed by environmental cues. The function of the GABA
neurons in the accumbens is moderated by dopaminergic input from the VTA, whose modulatory
effect is state dependent and may result in either increased or decreased activation of striatal
neurons depending in part on current glutamatergic and other neuromodulator input (Onn, West
& Grace, 2000). The GABAergic output neurons are also modulated by acetylcholine
interneurons and noradrenergic input (Hoebel, Avena, & Rada, 2007; Park, Aragona, Kile,
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Carelli, & Whiteman, 2010). These mechanisms may result in the capacity for the caudal core to
inflect the level of inhibitory output in either the positive or negative direction through the
integration of environmental information.
Unlike in previous studies assaying a topographical gradient in the accumbens shell, in the
current study there was no evidence of an inversion in the direction of the elicited of
approach/avoidance behaviour in the rostral core region such as that previously seen after
inactivation of rostral shell sites (Faure, Reynolds, Richards & Berridge, 2008; Reynolds &
Berridge, 2001). That is, the rostrally inactivated animals in the current study did not increase
their motivation to approach the reward cued environment above control levels.
A limitation in the interpretation of the current behavioural results with reference to a
rostrocaudal gradient in approach and avoidance was the qualitatively different nature of the
behaviour of the rostrally vs. caudally inactivated animals. As noted, the former animals
displayed lower total exploration times, which appeared to be largely mediated by a compulsive
chewing behaviour. Given that a significant percentage of time was spent chewing on an object
or surface, which was immediately in front of the rat, the animals may not have had a sufficient
opportunity to encounter the previously learned cues, explore the apparatus and display any
potential evaluative or motivational bias. However, chewing behaviour itself may be considered
to be more coherent which approach than avoidance behaviour, given that the animal is engaging
with, as opposed to moving away from the substrate. As such, the augmentation of this
behavioural pattern after rostral inactivation may in fact be supportive of a key role for rostral
core regions in eliciting approach behaviours. It is possible that the specific targeted rostral
coordinates constitute a site with connectivity to a structure representing motor output sequences
for chewing behaviour. The inactivation may have caused an inhibition of the GABAergic output
of the local medium spiny neurons, resulting in a release from inhibition of a particular
behavioural pathway. It is possible that other rostral core coordinates, perhaps also varying
mediolaterally and dorsoventrally, might mediate other appetitively valenced behaviours,
including Pavlovian approach to conditioned cues. This serves to highlight the necessity of
targeting and carefully specifying multiple coordinate sites in the determination of the functions
of the nucleus accumbens, particularly considering the historical neglect in the research literature
of more caudal accumbens sites. The varying behaviours elicited by manipulation of separate
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subregions is also coherent with the concept that this structure should be considered as a
composite of distinguishable neuronal ensembles, as opposed to in terms of a monolithic
function and output (Pennartz, Groenewegen, & Lopes da Silva, 1994).
The current study presented the animals with a juxtaposition of positively and negatively
valenced cues, which resulted in a requirement for the animal to make an approach/avoidance
decision in the face of opposing motivations. The question may arise as to whether differences
in the bias of the animals’ exploratory allotment were due either to an altered level of approach
or avoidance motivation. Previous studies which have assessed these poles of valence
independently have found evidence for both appetitive motivational (Berridge & Robinson,
1998; Roitman, Stuber, Phillips, Wightman, & Carelli, 2004) and aversive motivational
processing in the nucleus accumbens (Carlezon & Thomas, 2009; Levita et al., 2009;
McCutcheon et al., 2012). Moreover, in studies which have differentiated rostrocaudal locations
with respect to function, manipulations within a subregion have been found to simultaneously
affect discrete measures of appetitive and aversive motivation. (Faure, Reynolds, Richards &
Berridge, 2008; Reynolds & Berridge, 2001, Reynolds & Berridge, 2003). That is, it seems
possible that the bias toward aversion observed in the caudally inactivated animals is a composite
of a decreased motivational signal as well as an increased avoidance signal. In fact it may prove
difficult to dissociate the contribution to the two proposed poles of processing at the regional
pharmacological level. This caveat to interpretation is informed by several lines of evidence
from previous research. First, there is evidence from electrophysiological assessments that
separate neuronal populations of medium spiny neurons within the same region of the nucleus
accumbens code for values of cues associated with reward vs. punishment (Roitman, Wheeler &
Carelli, 2005). This suggests that the GABAergic manipulation at regional level could
theoretically have affected both neuron population types. An additional consideration when
interpreting electrophysiological studies is the specific targeted coordinate site of the accumbens
from which the recordings are taken. In the study by Roitman, Wheeler and Carelli (2005) for
example, the anteroposterior coordinate was at +1.7mm relative to bregma, rendering it close to
the rostral coordinate in the current study. (The mediolateral and dorsoventral differed however
at 0.8 and -6.5 respectively). In this study, the authors found that a greater proportion of reward
cue-sensitive neurons exhibited phasic excitations than inhibitions, and that aversive cue-
sensitive neurons exhibited a similar proportions of excitation relative to inhibition subgroups. It
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would be interesting to note whether the populations of neurons displaying increasing vs
decreasing activity in response to cues would inverse in the majority in more caudal regions of
the accumbens.
Additionally, there is evidence supporting the existence of some neuronal populations whose
activity patterns demonstrate that they have integrated information about both cost and benefit in
decision-making paradigms (Roesch et al., 2009). This further serves to highlight the fact that
nucleus accumbens subregions should not be considered as dichotomously aversive or appetitive
information processing locations, but that complex integrations and reiterations of valence are
likely to occur. Similarly supporting the notion of value integration at the level of the nucleus
accumbens, a functional magnetic resonance imaging study in humans has demonstrated that
cue-associated activity in the ventral striatum was modulated by the net value (calculated as the
expected reward value minus effort-based cost) of the upcoming decision (Croxson et al., 2009).
The concept of cost has most frequently been quantified in terms of the effort required to obtain
a reward, or through measuring delay discounting, wherein a reward diminishes in value
hyperbolically as the delay to obtain it increases. The accumbens may receive input that already
reflects the integrated value of certain costs and benefits. For example, individual dopaminergic
neurons in the rodent’s ventral tegmental area (VTA) as recorded by Roesch and Bryden (2011)
appeared to respond in a manner which reflected the integration of reward magnitude and delay.
A population of neurons in the ventral striatum, which receives dopaminergic input from the
VTA, also encoded both of these variables. Similarly, Day, Jones and Carelli (2011) found that a
subgroup of neurons in the nucleus accumbens displayed phasic firing rates which reflected the
cost-discounted value of the upcoming response in an effort-based, but not in a delay-based
decision-making task. The activation of other subgroups did not did not correlate with the cost-
discounted value, but instead appeared to be associated with response initiation, reward delivery,
the sustainment of high effort requirements or during waiting for delayed rewards. This serves to
illustrate the fact that the nucleus accumbens performs many distinguishable functions in the
activation of reward directed behaviour. In the foregoing study, the coordinate location in the
core from which measurements were taken was at an AP location of 1.3mm rostral to bregma,
rendering it relatively central with respect to the two anteroposterior coordinates assessed in the
current study. It remains to be determined whether the characterization of firing patterns would
be differentiable at other targeted sites in the accumbens.
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The current study may also be considered in relation to research investigating the neural
substrates of decision making under conditions of risk or uncertainty. While our study does not
systematically vary the probability of reward or punishment, and thus the emphasis is not on the
dimension of uncertainty, there is nonetheless likely a component of risk that is processed by the
animals in this task. The arrangement of the cues in the conflict tests is a novel configuration for
which the rats have not previously experienced any valenced outcome. During initial habituation
the animals are exposed to these juxtaposed cues without any programmed contingencies, and for
the duration of their training they encounter the cues and their associated outcomes in isolation
with respect to valence. When the animal encounters the conflicting cues during testing, there is
therefore a degree of uncertainty in the potential outcome. Neuroimaging studies in humans have
suggested a role for the nucleus accumbens in mediating risk-associated processing, such as
measured during gambling tasks. For example, several studies have found that higher levels of
activation in the accumbens during deliberation was associated with the choice of a riskier
opportunity for reward (Kuhnen & Knutson, 2005; Matthews, Simmons, Lane, & Paulus, 2004).
Some animal studies have also supported a role for the accumbens in biasing behaviour toward
riskier decisions. An experiment by Cardinal and Howes (2005) found that lesions of the nucleus
accumbens core resulted in an increased aversion to risk in a decision-making task, rendering the
animals more likely to prefer a smaller, certain reward versus a larger reward which was
dispensed with varying probability. In that study, the lesions to the accumbens extended
throughout the majority of the rostrocaudal axis of the core (from AP 0.7 to 2.2 mm relative to
bregma) in all subjects, with significant damage also extending to medial regions of the shell.
Thus it is unclear which subregion may have contributed to the behavioural effect. After finding
similar results when temporarily inactivating the entire nucleus accumbens via the infusion of a
GABA agonist, Stopper and Floresco (2011) attempted to further refine the localization of the
effect by using smaller volumes of the GABA agonist, thereby limiting its spatial spread to the
subregions of core vs. shell. It was found that inactivation of the shell recapitulated the risk
aversion observed when inactivating the broader structure, whereas inactivation of the core did
not result in a risk aversion deviating from control animals. It should be noted that the
anteroposterior coordinates of 1.5mm targeted in their study was closest to rostral, as opposed to
the caudal, coordinates targeted in the current study. Given that the rostrally inactivated animals
in the current study did not demonstrate a significantly deviated bias in their approach-
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avoidance behaviour as compared with controls, the results of the two studies may be
correspondent, to the extent that the current behavioural task may be appropriating the same
circuitry used in cost-benefit decision making under uncertainty. It is possible that risk-taking
behaviour as measured by Stopper and Floresco (2011) may be differentially altered if
inactivations were to be performed in more caudal regions of the core.
The elicitation of a compulsive chewing behaviour in animals undergoing inactivation of the
rostral core in the current study may be of interest beyond the possible interpretation of this
effect as a type of augmented appetitive response. The chewing observed in the rats was unusual
in that it was directed toward substrates that control animals did not normally chew upon,
including apparatus edges, body parts and the fur of cage-mates. Additionally, many animals
exhibited chewing motions even in the absence of any substrate in their mouths. Incidentally, this
type of behaviour has previously been characterized and is in fact used as a primary measure in
animal models of tardive dyskinesia. In humans, tardive dyskinesia is a disorder of involuntary
repetitive movements that can develop in patients undergoing long-term treatment with
dopamine antagonists most commonly used as antipsychotics medications. The symptoms most
frequently involve the orobuccal and lingual facial muscles (Sachdev, 2000). The syndrome has
been modelled in rats exposed to antipsychotic medications who demonstrate increased vacuous
chewing movements; that is, compulsive and repetitive chewing motions in the absence of
normal substrates (Kulkarni & Naidu, 2001). While some research has focused on potential
dopamine receptor aberrations in light of the primary target of the medications, there is some
evidence to suggest that deviations in the GABAergic system may be associated with this
condition (Gunne, Häggström, & Sjöquist, 1984; Inada et al., 2008). Thus it is possible that the
current site targeted in the rostral accumbens core is a key location involved in eliciting the
symptoms of tardive dyskinesia, possibly resultant from an aberration of GABA signalling
therein.
The differential effects of inactivation in the rostral vs. caudal accumbens core may result from
their distinctive rostrocaudal patterns of afferent and efferent input, given that these regions have
been found to have differential connectivity with multiple structures. For example, the ventral
region of the subiculum has been found to project predominantly to the caudomedial region of
the accumbens, whereas progressively more dorsal regions of the subiculum project to
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successively more lateral and rostral areas of the accumbens (Brog, Salyapongse, Deutch, &
Zahm, 1993). In addition, afferent projections from specific hippocampal regions have been
found to converge together with inputs from particular sub-nuclei of the basal amygdaloid
complex in a site-specific manner: In the rostral accumbens there is a convergence of inputs
from the intermediate septotemporal hippocampus and the intermediate rostrocaudal amygdala,
whereas in the caudal accumbens, there is a convergence between projections from the ventral
hippocampus and the caudal basal amygdaloid complex (Groenewegen, Wright, Beijer, &
Voorn, 1999). Tract tracing experiments have also revealed a topographical organization of the
efferent connections originating in the prefrontal cortex and terminating in NAc subregions along
rostral-caudal and mediolateral axes. For example, the medial orbitofrontal cortex (OFC) has
been found to project preferentially to the rostral accumbens whereas the lateral OFC has been
found to project to the more caudal accumbens regions. (Berendse, Graaf & Groenewegen,
1992). Given that the prefrontal cortex, amygdala and hippocampus have been implicated in
valuation and decision-making (Bechara, Damasio & Damasio, 1999; Johnson, van der Meer &
Redish, 2007) future experiments should examine the functional connectivity between
subregions of the nucleus accumbens and the specific target sites of their projections in order to
determine whether localized circuits preferentially mediate approach vs. avoidance behaviours.
The observed functional differences in the rostral and caudal core may also be mediated by
differences in neurotransmitter receptor distributions. One example is that norepinephrine
signalling has been found to be restricted to the caudal accumbens in rodents (Park, Aragona,
Kile, Carelli, & Whiteman, 2010). In an interesting study of the human brain, it was found that
the caudal subdivision of the accumbens selectively contains strikingly high levels of
noradrenaline, and the authors state that this site represents the only area in the human brain
expressing equally high levels of both noradrenaline and dopamine (Tong, Hornykiewicz, &
Kish, 2006). A rostrocaudal gradient has been found in dopamine D1 as well as D2 receptors, in
that the density of both subtypes has been found to be greater in the rostral as opposed to the
caudal regions (Richfield, Young, & Penney, 1987). The effects of agonizing or antagonizing
dopamine D1 or D2 and noradrenergic receptors in rostral vs. caudal accumbens regions might
therefore be investigated, especially considering the evidence of a role for dopamine in
mediating both reward-directed and aversive behaviours (Lammel, Lim & Malenka, 2014) and
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for norepinephrine in mediating the processing of motivational salience and anxiety (Bremner,
Krystal, Southwick & Charney, 1996; Ventura et al., 2008).
The results of the current study emphasize the importance of taking measurements or performing
manipulations in multiple subregions of the nucleus accumbens in order to fully characterize the
topography of its heterogeneous functions. One future direction would include a probing of
additional coordinate sites along the anteroposterior, mediolateral and/or dorsoventral axes using
the current paradigm in both the nucleus accumbens shell and core. Additionally, it would be
informative to test the effects of the current pharmacological manipulation on the acquisition of
conditioned cue preference, given previous evidence suggesting that the acquisition and
expression of motivated behaviours may be differentially represented within the accumbens. It
may be the case that GABAR manipulations in the accumbens shell would have a greater impact
on the acquisition of cue preference using the current paradigm, given the evidence supporting a
role for the shell in primary reward and reward-cue learning (Ito et al., 2001). Studies of finely
localized functional connectivity with other brain regions as outlined above will further elucidate
the representation and processing of valence in the brain.
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Figure 1. A test of training for cue valence demonstrated that animals spent a greater amount of time in the appetitive vs. the neutral cued arm, t(33) = 2.46 , p = .019, and less time in the aversive as compared with the neutral arm, t(33) = 6.39, p = < .001
Figure 2. In a test for cue valence training, there were no significant main effects found for cannula location, F(1, 30) = .72 , p = .40 or drug condition, F(1, 30 ) = .257, p = .62, nor were there any significant interactions, indicating that the groups did not exhibit any pre-existing differences in learning after training.
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Figure 3. Results of the conflict test in animals undergoing caudal core inactivation revealed that saline animals did not differ significantly in the time spent exploring the conflict versus neutral arms, F(1, 14) = 1.91, p = .19, whereas the inactivated animals spent significantly less time in the conflict as opposed to the neutral arm, F(1, 14) = 15.82, p = .001
Figure 4. Results of the conflict test in animals undergoing rostral core inactivation indicated that the saline group did not differ in time spent exploring the conflict versus neutral arms, F(1, 17) = .053, p = .82. There was no statistically significant difference in the inactivation group in time spent in the neutral as opposed to the conflict arm, F(1, 17) = 2.99 , p = .10.
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Figure 5. A test of novelty preference revealed that saline animals spent a greater amount of time in the novel arm, t(7) = 2.72 , p = .030, indicating a preference for novelty. While animals undergoing inactivation in the caudal core spent a greater amount of time in the novel as opposed to familiar arm, the difference was not statistically significant, t(5) = .36, p = .73.
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Diagram 1. Radial arm maze apparatus. For all training sessions, the walls of each arm were lined with a panel cue predictive of sucrose reward, footshock, or no outcome. During the final preference test, rats were allowed access to all three arms for a period of 5min. Neither sucrose nor footshock were administered.
Diagram 2. Radial arm maze apparatus. During the final conflict test, rats were allowed access to two arms for a period of 5min. One arm contained a superposition of cues predictive of sucrose reward and footshock, whereas the other arm contained the neutral cue. Neither sucrose nor footshock were administered.
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Diagram 3. Novelty preference apparatus during exposure phase. . At the beginning of the exposure phase, animals were introduced to the central hub of the radial maze for a thirty second habituation period. Doors to two arms were subsequently opened, and for 10 min the rats were free to explore the arms, which were characterized by distinct visual patterns on their walls (black and white circles, diagonal, or horizontal lines).
Diagram 4. Novelty preference apparatus during testing phase. During the testing phase, animals were returned to the apparatus for 5 min, whereupon three arms will be open, two of which contained the previously observed cues and one of which contained a novel pattern. The average time spent exploring the familiar arms was measured and compared with that spent exploring the novel arm.
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Diagram 5. Schematic representation of the locations of injector tips in the NAc rostral (left) and caudal (right) core based on the stereotaxic atlas of the rat brain of Paxinos and Watson (1997).
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