DOI 10.1515/revneuro-2012-0070   Rev. Neurosci. 2012; aop

Arianna Rinaldi , Alberto Oliverio and Andrea Mele*

S patial memory, plasticity and nucleus accumbens Abstract: Research on the function of the nucleus accum-

bens, the most ventral component of the striatal complex,

has traditionally focused on locomotor activity, reward,

motivation and addiction. However, based on the exist-

ence of projections to the nucleus accumbens from the

allocortical regions involved in spatial navigation, it has

been suggested that this structure plays a role in spatial

learning and memory. Lesion and neuropharmacologi-

cal studies confirm this view, also revealing the complex

dynamics of the receptors involved in these processes.

Moreover, the effects of post-training intra-nucleus

accumbens drug administrations demonstrate the neces-

sity of off-line neural activity within this structure in order

to consolidate spatial memory. Blockade of molecular

processes implicated in synaptic plasticity, such as cAMP

response element-binding protein (CREB)-induced tran-

scription or extracellular matrix remodeling, provides

further experimental support to this hypothesis. These

observations imply that experience-dependent synaptic

plasticity responsible for long-term stabilization of spatial

information might occur within the nucleus accumbens,

similarly to what has been observed in the hippocam-

pus. This suggests that a comprehensive understanding

of spatial memory processing should be viewed in the

context of a wider neural circuit.

Keywords: CREB; dopamine; glutamate plasticity; long-

term depression; long-term potentiation.

*Corresponding author: Andrea Mele, Dipartimento di Biologia e

Biotecnologie, Centro di Ricerca in Neurobiologia ‘D. Bovet’,

Sapienza Universit à di Roma, P.le Aldo Moro 5, 00185 Rome, Italia,

e-mail: andrea.mele@uniroma1.it

Andrea Mele: Dipartimento di Biologia e Biotecnologie, Centro di

Ricerca in Neurobiologia ‘D. Bovet’, Sapienza Universit à di Roma, Rome,

Italia; and Istituto Biologia Cellulare e Neurobiologia, CNR, Rome, Italia

Arianna Rinaldi: Dipartimento di Biologia e Biotecnologie, Centro

di Ricerca in Neurobiologia ‘D. Bovet’, Sapienza Universit à di Roma,

Rome, Italia; Istituto Biologia Cellulare e Neurobiologia, CNR, Rome,

Italia; and Centre for Integrative Physiology, University of Edinburgh,

Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK

Alberto Oliverio: Dipartimento di Biologia e Biotecnologie, Centro di

Ricerca in Neurobiologia ‘D. Bovet’, Sapienza Universit à di Roma,

Rome, Italia; and Istituto Biologia Cellulare e Neurobiologia, CNR,

Rome, Italia

Introduction The striatal complex is a heterogeneous structure that

has been distinguished into a more dorsal component,

or striatum proper, and a ventral division, which is gen-

erally referred to as nucleus accumbens (NAc). Several

cytological and neuroanatomical features differenti-

ate the dorsal and ventral striatum, but historically this

dichotomy has been mainly based on their different input-

output organization. Heimer and Wilson (1975) were the

first to recognize that although the dorsal striatum is the

primary target of sensory and motor cortices, the ventral

component receives most of its innervation from allocorti-

cal regions. The NAc receives dense glutamatergic projec-

tions from pyramidal cells in the prefrontal cortex (PFC)

(McGeorge and Faull, 1989; Groenewegen et al., 1990)

and from other limbic structures, such as the amygdala

(Kelley et al., 1982), the hippocampus (Kelley and Dome-

sick, 1982; Meredith et al., 1990) and the entorhinal cortex

(Finch et al., 1995). The NAc also receives excitatory inputs

from the thalamus (Kelley and Stinus, 1984; Berendse and

Groenewegen, 1990) and inhibitory projections from the

ventral pallidum (Churchill and Kalivas, 1994). Another

very important source of inputs is the ventral tegmental

area (VTA), which sends to the NAc dopaminergic projec-

tions (Fallon and Moore, 1978; Swanson, 1982) that have a

critical role in the mechanisms of action of natural rewards

and addictive drugs (Robbins et al., 2008). The NAc can

exert a strong direct and indirect feedback influence on

corticolimbic and mesencephalic afferents by means of

his output projections, which are primarily directed to the

ventral pallidum, the VTA and the substantia nigra (Nauta

et al., 1978; Berendse et al., 1992b).

The NAc can be distinguished into two distinct com-

partments, the core and the shell, based upon differ-

ences in their connectivity and in neurochemical markers

(Z á borszky et al., 1985; Zahm and Brog, 1992). The core is

the main target of the prelimbic region of the PFC, whereas

the shell receives mostly infralimbic PFC projections (Ber-

endse et al., 1992a; Heidbreder and Groenewegen, 2003).

The CA1 and the subiculum project mainly to the shell, but

some connections with the core have also been described

(Groenewegen et al., 1987; Berendse et al., 1992a; Brog et al.,

2   A. Rinaldi et al.: Spatial memory and nucleus accumbens

1993; Montaron et al., 1996; Heidbreder and Groenewe-

gen, 2003). The core preferentially sends projections to

the ventromedial region of the vental pallidum and to the

substantia nigra, whereas the main targets of the shell are

the dorsolateral compartment of the ventral pallidum and

the VTA (Nauta et al., 1978; Berendse et al., 1992b; Zahm

and Heimer, 1990). The NAc shell shares neuroanatomical

features with the amygdala, and it is indeed considered by

some authors as a component of the so-called extended

amygdala (de Olmos and Heimer, 1999). On the contrary,

the core is more similar to the medial dorsal striatum

(Zahm and Brog, 1992). It should indeed be noted that

there is no clear neuroanatomical segregation between

the dorsal and the ventral striatum. This lack of discrete

boundaries suggested a re-ordering of the striatal map

along a dorso-lateral to ventro-medial axis (Voorn et al.,

2004). Although the debate on the boundaries of stri-

atal sub-divisions is still open, the distinction between

dorsal and ventral striatum, based on their different cor-

tical inputs, has provided the conceptual framework for

remarkable advances in the knowledge of basal ganglia

function. Based on the allocortical inputs to the NAc,

Mogenson et al. (1980) envisaged this region as a “ limbic-

motor interface ” , opening the way to the proposal that the

NAc could be involved in the modulation of functions pre-

viously attributed only to upstream limbic regions.

The unique pattern of neural connections between

the NAc and cortico-limbic structures known to be

involved in spatial navigation has led to the hypothesis

that this structure might be involved in spatial informa-

tion processing. Particularly relevant are the projections

from the hippocampus and the entorhinal cortex, in light

of the well-documented role of these structures in spatial

navigation. Place cells in the CA1 (O ’ Keefe and Dostrovsky,

1971) and grid cells in the entorhinal cortex (Hafting et al.,

2005) encode information about the animal ’ s location and

lesions of these structures profoundly affect spatial learn-

ing and memory in rodents (Riedel et al., 1999; Parron and

Save, 2004; Yasuda and Mayford, 2006). Interestingly,

cells sensitive to the spatial location of the animal have

also been described in the NAc (Lavoie and Mizumori,

1994).

The purpose of this article is to review experimental

evidence of the role of the NAc in spatial learning and

memory, focusing on relevant molecular mechanisms.

First, we will describe how neurotransmitters modulate

neuronal activity and synaptic plasticity in the NAc. Then,

we will examine the effects of lesions or pharmacological

manipulations of the NAc on spatial information process-

ing and findings supporting the occurrence of learning-

induced synaptic plasticity in this structure.

Synaptic transmission and plasticity in the nucleus accumbens

The NAc consists of a rather small number of cell types.

The medium-sized spiny neurons (MSNs) are the main cell

type in this brain region, as well as in the dorsal striatum,

representing between 85% and 95% of the total cell popu-

lation (Gerfen, 1988; Tepper and Bolam, 2004; Tepper

et al., 2004). The rest of the NAc is composed of various

classes of interneurons, predominantly GABAergic

fast-spiking and cholinergic tonically active interneu-

rons, which exert a strong influence on MSNs excitabi-

lity (Gerfen, 1988; Tepper and Bolam, 2004; Tepper et al.,

2004).

Medium spiny neurons are GABAergic projection

neurons and represent the sole NAc output. MSNs are the

main target of inputs to the NAc, thus they have a crucial

role in the detection, integration and transmission of

behaviorally relevant information in this region. Different

populations of MSNs can be distinguished based on their

specific expression of receptors, channels or peptides

(Graybiel, 1990; Gerfen, 1992; Kawaguchi, 1993; Lu et al.,

1998). Both ionotropic and metabotropic glutamate recep-

tors are present in the NAc (Albin et al., 1992; Testa et al.,

1994). N-methyl- D -aspartate (NMDA), α -amino-3-hydroxy-

5-methyl-4-isoxazolepropionic acid (AMPA) and kainate

receptors are expressed at high levels on postsynaptic ter-

minals (Albin et al., 1992). The GluR1, GluR2 and GluR3

AMPA subunits are particularly abundant in NAc MSNs,

whereas the predominant NMDA subunits are NMDAR1

and NMDAR2B (Albin et al., 1992; Standaert et al., 1994;

W ü llner et al., 1994). Medium spiny neurons also express

high levels of group I, II and III metabotropic glutamate

receptors (mGluR), with mGluR5 being the most abundant

(Shigemoto et al., 1993; Testa et al., 1994). The MSNs of

the NAc, like those of the dorsal striatum, can be divided

into two major classes based on their output connections

and expression of dopamine (DA) receptors. Neurons that

project directly to the ventral mesencephalon express D1

DA receptors, whereas neurons that project to the ventral

pallidum express D2 DA receptors (Lu et al., 1998). Other

important neurotransmitters that are expressed in the

NAc, such as γ -aminobutyric acid (GABA), serotonin,

acetylcholine, endocannabinoid and opioid, will not be

included in this review, as their role in mediating spatial

information processing in the NAc has not yet been well

characterized.

Intracellular recordings from slices in vitro and

from anesthetized animals show that MSNs in the NAc

are predominantly quiescent with very low levels of

A. Rinaldi et al.: Spatial memory and nucleus accumbens   3

spontaneous firing, and many of them exhibit a bistable

membrane potential similar to MSNs in the dorsal stria-

tum (Wilson and Groves, 1981; O ’ Donnell and Grace, 1995).

Their resting membrane potential is highly hyperpolarized

(down state) and is periodically interrupted by subthresh-

old depolarizations (up states) associated with a higher

probability of spiking (Nisenbaum and Wilson, 1995;

O ’ Donnell and Grace, 1995; Kreitzer, 2009). Similar mem-

brane potential fluctuations have been observed in dorsal

striatal MSNs in non-anesthetized rats, but only during

slow-wave sleep (Mahon et al., 2006). In contrast, awake

animals showed a unimodal membrane potential, charac-

terized by temporally disorganized depolarizing events of

variable amplitude and duration associated with irregu-

lar firing patterns (Mahon et al., 2006). It seems indeed

that the arousal state of the animal might be an important

determinant of the excitability of NAc neurons (Callaway

and Henriksen, 1992; Wolf et al., 2009), and more studies

in awake animals will be necessary to elucidate the occur-

rence and relevance of NAc MSNs state transitions in vivo .

The mechanisms of synaptic inputs integration in NAc

MSNs are still debated, but there is a general agreement

that MSNs require strong and correlated glutamatergic

inputs to reach the firing threshold (Pennartz et al., 1994;

O ’ Donnell and Grace, 1995; O ’ Donnell et al., 1999). Neuro-

anatomical tracing and neurophysiological studies show

a high degree of convergence of different excitatory inputs

onto MSNs (Brog et al., 1993; O ’ Donnell and Grace, 1995;

Finch, 1996; Groenewegen et al., 1999), which suggests

that the NAc could behave as a coincidence detector (Wolf

et al., 2009). Alternatively, the ‘ gating ’ theory proposes

that the membrane potential transitions of MSNs func-

tion as a binary gate that allows the flow of information

only when the cell is in the depolarized state (O ’ Donnell

and Grace, 1995). According to this model, hippocampal

afferents would be responsible for driving a distributed

set of NAc neurons into the up state, allowing them to fire

in response to ongoing cortical activity. However, recent

data showing that prefrontal inputs also can promote the

transition from the down to the up state suggest the need

to revise this model (Gruber and O ’ Donnell, 2009).

Dopamine is a crucial modulator of the excitability

of NAc neurons. Studies of DA action in vivo show that it

attenuates the synaptic responses evoked by stimulation of

NAc excitatory efferents, such as the hippocampus (Yang

and Mogenson, 1984), the amygdala (Yim and Mogen-

son, 1982) or the prefrontal cortex (Brady and O ’ Donnell,

2004). The results obtained in slice preparations in vitro

are less consistent and suggest that DA, in some experi-

mental conditions, can also enhance synaptic responses

(Uchimura et al., 1986; Pennartz et al., 1992; O ’ Donnell

and Grace, 1996). Dopaminergic and glutamatergic inputs

form synapses in close proximity on MSNs (Freund et al.,

1984; Sesack et al., 2003). This convergence of inputs

enables DA and glutamate signals to interact, and inte-

gration of these signals seems to be important for MSNs

excitability and synaptic plasticity (Cepeda et al., 1993;

Pennartz et al., 1994; Schotanus and Chergui, 2008a).

For example, glutamate- or AMPA-induced responses in

neostriatal rat slices are significantly attenuated by ionto-

phoretic DA application, an effect mimicked by the D2 DA

receptor agonist quinpirole. In contrast, NMDA-induced

responses are enhanced by administration of DA or the D1

DA receptor agonist SKF 38393 (Cepeda et al., 1993). These

results suggest that DA action, and how DA and glutamate

interact, might depend on the receptor subtypes or the

afferents involved, as well as on the state of activity of the

system.

Long-term potentiation (LTP) and long-term depres-

sion (LTD) of excitatory synaptic transmission have both

been described in the NAc. In slice preparations contain-

ing prefrontal cortex-NAc synapses, tetanic stimulation

of prefrontal inputs induces LTP of both extracellularly

recorded field excitatory postsynaptic potentials (EPSP)

and intracellularly recorded EPSPs in the NAc (Pennartz

et al., 1993; Kombian and Malenka, 1994). Long-term

potentiation of field potentials could also be elicited by

tetanic stimulation of the fimbria-fornix in anesthetized

rats in vivo (Boeijinga et al., 1993). Long-term poten-

tiation in the NAc is blocked by bath application of the

NMDA receptor antagonist D-2-amino-5-phosphonovaler-

ate (AP-5) and the calcium chelator 1,2-bis(2-aminophe-

noxy)ethane-N,N,N ′ ,N ′ -tetraacetic acid (BAPTA), thus it

is dependent on NMDA receptors and requires a rise in

intracellular calcium concentration (Pennartz et al., 1993;

Kombian and Malenka, 1994). Selective pharmacological

inhibition of either NR2A or NR2B NMDA receptor sub-

units, mGluR1 or mGluR5 prevents LTP in the NAc, which

suggests that activation of both NR2A- and NR2B-contain-

ing NMDA receptors and of group I mGluRs is necessary to

induce NAc LTP (Schotanus and Chergui, 2008a, b).

More controversial is the involvement of DA recep-

tors in the induction of LTP in NAc MSNs. An early study

from Pennartz et al. (1993) did not find any effect of DA,

SCH 23390 (a D1 receptor antagonist) or sulpiride (a D2

receptor antagonist) on NAc LTP. However, a more recent

study using higher concentrations of the DA receptor

antagonists showed that activation of DA D1 receptors,

but not D2, is required for LTP induction by tetanic stimu-

lation (Schotanus and Chergui, 2008a). It has also been

shown that bath application of higher concentrations of

DA or of DA reuptake blockers prevents the induction of

4   A. Rinaldi et al.: Spatial memory and nucleus accumbens

LTP by high-frequency stimulation of cortical afferents

(Li and Kauer, 2004; Schotanus and Chergui, 2008a).

Taken together these data suggest that an optimal DA con-

centration range is required for LTP in the NAc, as treat-

ments that either reduce or increase DA transmission are

detrimental to LTP generation in this region. Application

of the GABA A receptor antagonist bicuculline or the GABA

B

receptor antagonist CGP55845 did not affect the expres-

sion of LTP, ruling out a contribution of GABA to LTP in

the NAc (Schotanus and Chergui, 2008a).

Several forms of LTD have been described in the

NAc. Robust LTD of prefrontal-accumbal synapses can be

induced by low-frequency stimulation of the cortical affer-

ents coupled to a modest depolarization of the postsyn-

aptic cell (Brebner et al., 2005; Grueter et al., 2010). Long-

term depression of field EPSPs or intracellularly recorded

EPSPs can also be induced by tetanic stimulation of pre-

frontal afferents in the presence of the AMPA receptor

antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)

(Kombian and Malenka, 1994). Nucleus accumbens LTD

is NMDA-dependent and requires an increase in post-

synaptic calcium levels, but NMDA-independent LTD has

also been described in this structure. Robbe et al. (2002)

have found that low-frequency stimulation of prefrontal

inputs induced a presynaptic form of LTD, dependent on

endocannabinoid (eCB), CB1 receptors and mGluR5 acti-

vation. Recent data suggest the interesting possibility that

different MSN subtypes express different forms of LTD.

For example, LTD induction requires mGluR5 as well as

CB1 receptors, and transient receptor potential vanilloid

1 (TRPV1) channels activation in MSNs that express D2

DA receptors, but not in D1 expressing neurons (Grueter

et al., 2010). Dopamine receptors do not seem to be involved

in LTD induction in the NAc (Robbe et al., 2002; Grueter

et al., 2010).

Nucleus accumbens in spatial learning and memory The first evidence of the involvement of the NAc in spatial

information processing came from studies of lesions or

pharmacological manipulations of glutamate and DA

receptors in rodents. Pre-training ibotenic acid lesions of

the NAc impair the behavioral performance of rats trained

to locate a hidden platform in the spatial version of the

Morris water maze (MWM) navigation task (Annett et al.,

1989, but see also Floresco et al., 1996; Jongen-R ê lo et al.,

2003). Lesioned animals needed more time to find the

platform during training. After several training trials, they

eventually learned the platform location but they were still

impaired, relative to control non-lesioned rats, in a probe

test during which the escape platform was removed. Pre-

training NMDA-induced excitotoxic lesions of the NAc

produce a behavioral impairment in rats trained to search

for food in the baited arms of a radial-arm maze (Jongen-R ê lo

et al., 2003). Shell-lesioned, but not core-lesioned animals

showed an increase in the number of working memory

errors, defined as re-entries into arms already visited

during a single training trial. In contrast, reference memory,

measured as the number of first entries into unbaited

arms, was intact in both core- and shell-lesioned rats

(Jongen-R ê lo et al., 2003). Electrolytic or excitotoxic lesions

of the NAc in rats greatly reduce conditioned freezing to

a context, but not to a cue, previously associated with an

aversive stimulus (Riedel et al., 1997; Jongen-R ê lo et al.,

2003). Overall the effects of NAc lesions on spatial learn-

ing are less severe than those induced by hippocampal

lesions, nonetheless these findings indicate that, at least

in some experimental conditions, the integrity of the NAc

is necessary for correct spatial information processing.

Studies testing the effects of focal intra-NAc drugs

infusion, in different spatial learning tasks, provide

further support to the hypothesis that the NAc is involved

in spatial learning and memory. Administrations of

6,7-dinitroquinoxaline-2,3-dione (DNQX) and AP-5,

respectively AMPA and NMDA receptors competitive

antagonists, before temporally massed training in the

MWM, impair mice ’ s ability to correctly perform the task

(Ferretti et al., 2007). The massed schedule training, com-

prising four learning sessions and a probe test immediately

after the last training trial, lasted approximately 80 min,

thus preventing the mice from relying on long-term con-

solidated information to perform the task. Although both

treatments did not affect mice performance during train-

ing, blockade of either AMPA or NMDA receptors impaired

spatial localization during the probe test (Ferretti et al.,

2007). The role of AMPA and NMDA receptors in spatial

information processing in the NAc has been further inves-

tigated studying the effects of pre-training antagonists

administrations on the detection of a spatial change in the

object displacement task. This task, originally developed

by Poucet and colleagues (Poucet, 1989; Thinus-Blanc et

al., 1992), was designed to estimate the ability of rodents

to encode spatial relationships among discrete stimuli.

Animals are allowed to explore five objects placed at a

fixed location in an open field for three sessions of habitu-

ation, after which their reaction to the displacement of two

of these objects is examined (Poucet, 1989; Thinus-Blanc

et al., 1992; Roullet et al., 1996; Usiello et al., 1998). This

behavioral paradigm is particularly interesting because,

A. Rinaldi et al.: Spatial memory and nucleus accumbens   5

in contrast to other spatial learning tasks, rodents are

not required to constitute any kind of stimulus-response

association, and there is no explicit positive or negative

reinforcement. These features make it very well suited to

investigating the involvement of the NAc in spatial learn-

ing in light of the established role of this structure in

reward-related learning (Robbins and Everitt, 1996; Kelley

et al., 1997). When tested in the object displacement task,

animals usually show an increased exploration of the dis-

placed objects; this response is generally interpreted as an

index of the ability to detect and react to a spatial change

(Poucet, 1989; Thinus-Blanc et al., 1992). Pre-training

intra-NAc admini strations of AP-5 or DNQX impaired the

ability of mice to re-explore the displaced objects immedi-

ately after training (Coccurello et al., 2012), confirming the

deficits observed in the MWM. NMDA receptors blockade

selectively affected the detection of the spatial change and

did not affect the reaction of the mice to an object substi-

tution following the object displacement. On the contrary,

AMPA-antagonist-injected mice also showed a decrease in

exploration of the novel object (Coccurello et al., 2012).

Blockade of DA receptors in the NAc has an impair-

ing effect on the ability of laboratory rodents to perform

different spatial tasks, which suggests a facilitatory role

of ventral striatal DA on spatial information processing

(Ploeger et al., 1994; Coccurello et al., 2000). Pre-training

administrations of the non-selective DA antagonist halo-

peridol induced a deficit in the acquisition of the MWM

at doses that did not affect motor activity (Ploeger et al.,

1994). Pre-training intra-NAc administrations of SCH 23390

or sulpiride impaired the performance of mice in the object

displacement task (Coccurello et al., 2000). However, an

intra-NAc D2 receptors blockade not only impaired the dis-

crimination of the object displacement, but also induced a

reduction of all the other behavioral parameter analyzed,

which suggests that the effect observed could not be spe-

cifically attributed to impaired spatial learning, but rather

to more general ‘ regulatory impairments ’ similar to the one

described in the MWM after 6-OHDA lesions of the dorsal

striatum (Hagan et al., 1983; Winn and Robbins, 1985).

DA and glutamate terminals in the NAc converge on the

same dendritic spines of MSNs (Freund et al., 1984; Sesack

et al., 2003). This structural organization provides support

for a close interaction between the two systems in the

modulation of NAc functional output, and indeed electro-

physiological evidence demonstrates receptor-dependent

DA/glutamate interplay in the modulation of the activity of

MSNs in the dorsal striatum (Cepeda et al., 1993). To inves-

tigate whether the interaction of DA and glutamate recep-

tor subtypes within the NAc differentially modulate spatial

learning, Coccurello et al. (2012) investigated the effects of

intra-NAc pre-training admini strations of low subthresh-

old doses of D1 or D2 receptor antagonists, in combina-

tion with subthreshold doses of AMPA or NMDA receptor

antagonists. It was found that the concomitant infusion of

per se ineffective doses of D1/NMDA and D2/AMPA recep-

tor antagonists, but not D2/NMDA or D1/AMPA receptor

antagonists, specifically impaired the acquisition of spatial

information in mice tested in the object displacement task

with a short interval between training and testing (Coc-

curello et al., 2012). These results confirm the electrophysi-

ological evidence supporting a receptor subtype-depend-

ent heterologous interaction between DA and glutamate,

as well as preferential D1/NMDA and D2/AMPA interplay

in the modulation of NAc functional output (Cepeda et al.,

1993). However, the effects observed on spatial discrimina-

tion do not completely mimic those on neuronal responses

in terms of direction of the interaction. In fact, although

the cooperative effect observed after co-administrations of

NMDA and D1 antagonists in the object displacement task

(Coccurello et al., 2012) mirrors that induced by NMDA/

D1 receptor stimulation of MSN neural activity (Cepeda et

al., 1993), D2 receptor stimulation has been found to act

in an antagonist way on AMPA-induced electrophysiologi-

cal responses (Cepeda et al., 1993), which is opposite to

the positive interaction between the two receptor subtypes

observed in spatial learning (Coccurello et al., 2012).

Overall these findings demonstrate that both gluta-

mate and DA receptors located in the NAc play a role in the

acquisition of spatial information, and that specific inter-

actions among the different receptor subtypes are relevant

to this process.

Details of the contributions described in this as well

as in the next paragraph are summarized in Table 1 , which

also contains information about various experimental

conditions of each study.

NAC and experience-dependent plasticity Kelley and colleagues studying the effects of multiple intra-

NAc injections of AMPA and NMDA antagonists on the

ability of rats to retrieve food in the hole board task, found

an interesting difference between the two receptor sub-

types (Maldonado-Irizarry and Kelley, 1995). In fact, both

antagonists disrupted the search pattern of the animals;

however, whereas DNQX induced a memory deficit for

the spatial location of the food between consecutive trials

within a single training session, the AP-5 effect was more

evident between sessions performed over different days.

6   A. Rinaldi et al.: Spatial memory and nucleus accumbens

Task Training Manipulation Time of treatment ITI Effect Reference

FC (context) Distributed NMDA lesion (shell) Pre-training - Jorgen-Rȇlo et al., 2003

FC (context) Distributed NMDA lesion (core) Pre-training 0 Jorgen-Rȇlo et al., 2003

Hole board Distributed AP-5 (shell) Post-training - Maldonado-Irizarry and Kelley, 1995

Hole board Distributed AP-5 (core) Post-training − Maldonado-Irizarry and Kelley, 1995

Hole board Distributed DNQX (shell) Post-training - Maldonado-Irizarry and Kelley, 1995

Hole board Distributed DNQX (core) Post-training − Maldonado-Irizarry and Kelley, 1995

Hole board Distributed AP-5 (shell) Pre-training - Maldonado-Irizarry and Kelley, 1995

Hole board Distributed AP-5 (core) Pre-training − Maldonado-Irizarry and Kelley, 1995

Hole board Distributed DNQX (shell) Pre-training - Maldonado-Irizarry and Kelley, 1995

Hole board Distributed DNQX (core) Pre-training − Maldonado-Irizarry and Kelley, 1995

MWM Massed Supiride Post-training Long - Setlow and McGaugh, 1999

MWM Massed Lidocaine Pre-test Long 0 Floresco et al., 1996

MWM Distributed Haloperidol Pre-test 0 Ploeger et al., 1994

MWM Distributed Electrolytic Pre-test 0 Sutherland and Rodriguez, 1989

MWM Massed Lidocaine Pre-training Long 0 Floresco et al., 1996

MWM Distributed Haloperidol Pre-training - Ploeger et al., 1994

MWM Distributed Ibotenic lesions Pre-training - Annett et al., 1989

MWM Distributed Electrolytic Pre-training - Sutherland and Rodriguez, 1989

MWM Distributed NMDA lesion (shell) Pre-training 0 Jorgen-Rȇlo et al., 2003

MWM Distributed NMDA lesion (core) Pre-training 0 Jorgen-Rȇlo et al., 2003

OD Massed SCH23390 Post-training Long - Mele et al., 2004

OD Massed Sulpiride Post-training Long - Mele et al., 2004

OD Massed DNQX/SCH23390 Post-training Long - Ferretti et al., 2005

OD Massed DNQX/Sulpiride Post-training Long - Ferretti et al., 2005

OD Massed AP-5/SCH23390 Post-training Long - Ferretti et al., 2005

OD Massed AP-5/Supiride Post-training Long - Ferretti et al., 2005

OD Massed DNQX Pre-test Long - Roullet et al., 2001

OD Massed MK-801 Pre-training Short - Usiello et al., 1998

OD Massed DNQX/SCH23390 Pre-training Short 0 Coccurello et al., 2012

OD Massed DNQX/Sulpiride Pre-training Short - Coccurello et al., 2012

OD Massed AP-5/SCH23390 Pre-training Short - Coccurello et al., 2012

OD Massed AP-5/Supiride Pre-training Short 0 Coccurello et al., 2012

OD Massed SCH 23390 Pre-training Short - Coccurello et al., 2000

OD Massed Sulpiride Pre-training Short - Coccurello et al., 2000

OD Massed DA Pre-training Short 0 Coccurello et al., 2000

OD Massed Ibotenic Pre-training Short + Roullet et al., 1997

OD Massed Ibotenic Pre-training Short + Roullet et al., 1997

OD/MWM Massed DNQX Post-training Long 0 Roullet et al., 2001; Sargolini et al.,

2003a

OD/MWM Massed AP-5 Post-training Long - Roullet et al., 2001; Sargolini et al.,

2003a

OD/MWM Massed DNQX Pre-training Short - Ferretti et al., 2007; Coccurello

et al., 2012

OD/MWM Massed AP-5 Pre-training Short - Ferretti et al., 2007; Coccurello

et al., 2012

Radial maze Kynurenic acid Pre-test - Schacter et al., 1989

Radial maze AP-5, DNQX, Kynurenic

(shell)

Pre-test - (RM) Klein et al., 2004

Radial maze AP-5, DNQX, Kynurenic

(core)

Pre-test - (RM) Klein et al., 2004

Radial maze AP-5 (shell) Pre-test - (WM) Klein et al., 2004

Radial maze AP-5 (core) Pre-test 0 (WM) Klein et al., 2004

Radial maze DNQX, kynurenic (shell) Pre-test 0 (WM) Klein et al., 2004

Radial maze DNQX, kynurenic (shell) Pre-test 0 (WM) Klein et al., 2004

Radial maze Distributed AP-5 (shell) Pre-training 0 Smith-Roe et al., 1999

Radial maze Distributed AP-5 (core) Pre-training - Smith-Roe et al., 1999

Radial maze Distributed Ibotenic Pre-training + Roullet et al., 1997

Radial maze Distributed NMDA lesion (shell) Pre-training - (WM) Jorgen-Rȇlo et al., 2003

0 (RM)

A. Rinaldi et al.: Spatial memory and nucleus accumbens   7

Task Training Manipulation Time of treatment ITI Effect Reference

Radial maze Distributed NMDA lesion (core) Pre-training 0 Jorgȇn-Relo et al., 2003

Radial maze (RF) Lidocaine Pre-test - Seaman and Phillips, 1994

Radial maze (RF) Haloperidol Pre-test - Floresco et al., 1996

Radial maze (W-S) Lidocaine Pre-test - Seaman and Phillips, 1994

Radial maze (W-S) Haloperidol Pre-test 0 Floresco et al., 1996

Radial maze (W-S) Lidocaine Pre-training 0 Seaman and Phillips, 1994

Radial maze (W-St) Lidocaine Pre-test 0 Seaman and Phillips, 1994

T-maze Distributed Ibotenic lesions Pre-training - Annett et al., 1989

Table 1 Summary table of the effects induced by nucleus accumbens manipulations in spatial learning and memory tasks.

Task: MWM, Morris water maze; OD, object displacement; FC, fear conditioning; W-St, win-stay; W-S win-shift; RF, random foraging.

Training: massed, performed in 1 day; distributed, performed over multiple days. ITI, interval between training and testing; short,  < 60 min;

long, generally 24 h. Effect: -/ – , impairment; + , improvement; 0, no effect; WM, working memory; RM, reference memory.

Similar findings were reported after intra-NAc admini-

strations of AP-5 in animals trained in the radial arm maze

(Smith-Roe et al., 1999). Indeed, NMDA receptor blockade

in the core (but not in the shell) of the NAc induced an

increase in the number of reference memory errors, more

than trial-dependent working memory errors. Based on

these results, the authors suggested that AMPA receptors

located in NAc are needed to guide ongoing behaviors,

whereas NMDA receptors might play a role in memory

maintenance (Maldonado-Irizarry and Kelley, 1995; Smith-

Roe et al., 1999). It should be considered that the behav-

ioral paradigms used in these studies required multiple

days of training, and thus multiple acquisition, consolida-

tion and retrieval phases, not allowing an univocal inter-

pretation of the results. Nevertheless, these early findings

prompted the hypothesis that the NAc could be involved

not only in short-term processing of spatial information

(STM), but also in long-term spatial memory (LTM).

In the classical view of the memorization process, for-

mation of LTMs is believed to involve a dynamic process

by which a labile trace is progressively converted into a

more stabile and potentially permanent one (McGaugh,

1968, 2000; McGaugh and Herz, 1972). This transforma-

tion has been suggested to depend upon plastic changes

that involve a sequence of specific cellular processes

(Davis and Squire, 1984; Nguyen et al., 1994; Bailey,

1999). The first step in this cascade is the activation of

synaptic receptors, which triggers short-term changes in

synaptic efficacy based upon receptor phosphorylation

and trafficking. These early changes are then followed

by alterations in gene expression and protein synthesis,

pro-dromic to structural modifications, and sustained

by neural activity independently of direct environmental

stimulation (Dudai, 2002). Short-lasting and reversible

neuropharmacological manipulations, performed before

or immediately after training and associated with long

(Table 1 continued)

intervals between training and testing, represent a pow-

erful strategy to verify cellular and molecular processes

necessary for learning-induced plasticity.

The first evidence of the involvement of the NAc in

memory consolidation came from the finding that post-

training NAc administrations of tetratodoxin, a sodium

channel blocker, impair performance in the one-trial

inhibi tory avoidance task (Lorenzini et al., 1995). The require-

ment of NAc off-line neural activity for the long-term stabi-

lization of spatial information was investigated soon after

using massed training protocols, associated with post-

training neuropharmacological manipulations (Setlow

and McGaugh, 1999; Roullet et al., 2001). Post-training

intra-NAc AP-5 administrations reduced the re-exploration

of DOs in the object displacement task, as well as the ability

to correctly locate the platform in the probe trial of the

MWM, when mice were tested 24 h after training (Roullet

et al., 2001; Sargolini et al., 2003a). Interestingly, post-

training administrations of the AMPA antagonist DNQX

did not affect mice behavior in both tasks, which suggests

that activation of NMDA, but not AMPA, receptors located

in the NAc is needed to sustain off-line activity necessary

for long-term storage of information (Roullet et al., 2001;

Sargolini et al., 2003a). This observation raised the ques-

tion of whether the impairments induced by pre-training

blockade of AMPA receptors when a short time interval is

imposed between training and testing (Coccurello et al.,

2012) could extend to long-term storage of information. In

fact, it could be hypothesized that activation of both recep-

tor subtypes is required for long-term storage of spatial

information, but AMPA receptors are involved specifically

in the early stages of encoding. Recent experiments in the

authors ’ laboratory showing that pre-training adminis-

trations of the AMPA receptor antagonist NBQX induce

deficits in mice tested 24 h after training in the MWM (unpub-

lished observations) seem to support this hypothesis.

8   A. Rinaldi et al.: Spatial memory and nucleus accumbens

Post-training blockade of DA receptors in this region

impairs spatial memory, which is in agreement with the

involvement of these receptors in the induction of synaptic

plasticity in the NAc in in vitro models (Li and Kauer, 2004;

Schotanus and Chergui, 2008a). However, different from

what has been reported for high-frequency stimulation-

induced LTP (Schotanus and Chergui, 2008a), spatial defi-

cits were observed not only after administration of the D1

receptor antagonist SCH 23390 (Mele et al., 2004), but also

after post-training administration of the D2 receptors anta-

gonist sulpiride (Setlow and McGaugh, 1999; Mele et al.,

2004). Substantial evidence demonstrate that glutamate

and DA receptors interact to modulate the neural activi ty

of MSNs, not only at the electrophysiological level, but

also at the molecular level (Kelley, 2004). Intra-NAc post-

training co-administrations of ineffective doses of DA and

glutamate antagonists induced a spatial deficit in the object

displacement task when mice were tested 24 h after train-

ing (Ferretti et al., 2005). Interestingly the impairment was

independent of the combination of receptor subtypes. In

fact, mice injected with subthreshold doses of AP-5, DNQX,

SCH23390 or sulpiride were able to react to the object dis-

placement as well as control mice. On the contrary, animals

administered the different combinations of glutamate and

DA antagonists did not discriminate the spatial change

(Ferretti et al., 2005). This pattern of responses is differ-

ent from that observed after pre-training administrations

of the same drug combinations when a short time interval

is interposed between training and testing (Coccurello et

al., 2012). These differences could be due to the different

time window in which DA-glutamate receptor interaction

is needed to modulate the two kinds of memory (i.e., STM

and LTM). Alternatively, the distinct pattern of interaction

underlying the two processes may underscore the disso-

ciation between the cellular events sustaining short- and

long-term maintenance of information in this structure.

Taken together, these findings demonstrate that NAc off-

line neural activity is needed for spatial memory consoli-

dation, thus implying that experience-dependent synaptic

plasticity might occur within this structure for long-term

stabilization of spatial information. This hypothesis has

been addressed assessing the effects on spatial learning

and memory of intra-NAc manipulations of molecular pro-

cesses known to underlie hippocampal synaptic plasticity.

For example, experimental evidence suggests that protein

kinase C (PKC), which has been implicated in the initiation

and maintenance of LTP (Lovinger et al., 1987; Lovinger

and Routtenberg, 1988), could be a molecular substrate

of spatial learning in the NAc. Blockade of PKC during the

acquisition of a food-searching spatial task by intra-NAc

administration of either the inhibitor GF109203X or an

antisense-oligonucleotide (AS-ODN) targeted against PKC- γ

mRNA resulted in a mild deficit in the learning phase and a

stronger impairment of memory retention 48 h after the end

of training (Alvarez-Jaimes et al., 2004, 2005b). A similar

impairment was observed after blockade of the mitogen-

activated protein kinase (MAPK) by the inhibitor U0126

(Alvarez-Jaimes et al., 2005b). Different molecular events

shown to be crucial for hippocampal-dependent memory

formation, such as cAMP response element binding protein

(CREB) activity and de novo protein synthesis have also

recently been investigated in the NAc. CREB and Fos are

ubiquitous transcription factors required to trigger gene

expression underlying LTM consolidation (Bourtchuladze

et al., 1994; Seoane et al., 2012). Exposure to a novel envi-

ronment is associated with an increase in CREB phospho-

rylation (Alvarez-Jaimes et al., 2005a) and Fos levels in

the NAc (Rinaldi et al., 2010). Intra-NAc administrations

of AS-ODN targeted against CREB impaired long- but not

short-term spatial memory in the object displacement task

( Figure 1 ) (Ferretti et al., 2010). A similar impairment of

LTM in the object displacement task and in the MWM has

been observed after post-training intra-NAc injection of

the protein synthesis inhibitor anisomycin (Ferretti et al.,

2010). Taken together, these data demonstrate that CREB-

induced transcription and protein synthesis in the NAc are

required for spatial memory. It has not yet been investigated

if spatial learning can induce structural plasticity in the

NAc; however, inhibition of extracellular proteolytic activ-

ity in this brain region impairs long-term spatial memory

(Ferretti et al., 2010). Indeed, intra-NAc administration of

the inhibitor of the extracellular proteases tissue plasmino-

gen activator (tPA), PAI-1, impaired the performance of mice

in the object displacement task and in the MWM (Ferretti

et al., 2010). Interestingly, this effect was specific for long-

term spatial memory as the same treatment did not affect

performance when mice were tested only 30 min after train-

ing (STM) or in the cued version of the maze 24 h after train-

ing (Ferretti et al., 2010).

These results support the view that spatial learning

and memory depend not only on the ability of DA and

glutamate receptors located in the NAc to sustain off-line

neural activity, but also on the occurrence in this brain

structure of key molecular steps described to be crucial in

in vitro models of synaptic plasticity as well as in experi-

ence-dependent plasticity in the hippocampus.

Conclusions In this paper, we have briefly reviewed evidence pointing

to a role of the NAc in spatial learning and memory and

A. Rinaldi et al.: Spatial memory and nucleus accumbens   9

showing the occurrence of experience-dependent plastic-

ity within this structure. Since the early studies by Mogen-

son and colleagues (Schacter et al., 1989) our confidence

in a role of the NAc in the different stages of spatial infor-

mation processing has progressively increased. The entire

repertoire of molecular processes occurring in the NAc to

sustain memory formation still needs to be unveiled in

its complexity, but some early suggestions seem to stand

experimental verification and have been detailed by more

recent studies. For example, the original suggestion of an

involvement of NAc glutamate receptors in spatial learning

and memory has been expanded by findings demonstrat-

ing that AMPA receptors activity is needed only in the early

phases of spatial information encoding, whereas blockade

of NMDA receptors is also effective at later stages (Sargolini

et al., 2003a; Ferretti et al., 2007). Neuropharmacological

studies also revealed the complex dynamic of the heter-

ologous interplay between DA and glutamate receptors in

the NAc in the different stages of the memorization process

(Ferretti et al., 2005; Coccurello et al., 2012), suggesting

that distinct interactions might underlie early and late

phases of memory stabilization.

A further aspect that has not yet been completely

explored from a functional point of view is the neuro-

anatomical and cellular heterogeneity of the NAc. For

example, despite some evidence demonstrating a prefer-

ential role of the core rather than the shell in the process-

ing of spatial information (Maldonado-Irizarry and Kelley,

1995; Jongen-R ê lo et al., 2003; Klein et al., 2004), this

difference has not been observed in all behavioral tasks

(Jongen-R ê lo et al., 2003). Also potentially interesting is

the effect of shell manipulations on working- rather than

reference-memory reported in some, but not all, studies

(Jongen-R ê lo et al., 2003; Klein et al., 2004; but see also

Smith-Roe et al., 1999). These inconsistencies and the

scarcity of studies addressing this issue make it diffi-

cult to draw firm conclusions on the specific role played

by NAc sub-divisions in spatial learning and memory

(Maldonado-Irizarry and Kelley, 1995; Jongen-R ê lo et al.,

2003; Klein et al., 2004). Moreover, other aspects of NAc

heterogeneity, such as patches and matrix compartments,

have never been thoroughly explored for their specific

contribution to the processing of spatial information.

Experimental findings pointing to off-line neural

activity necessary for spatial memory consolidation

(Lansink et al., 2009) and learning-induced plastic

processes within the NAc (Alvarez-Jaimes et al., 2004,

2005a,b; Ferretti et al., 2010) raise several interesting

10

A

B

6

Mea

n tim

e of

con

tact

S5-

S4

(s)

2

-2

-6

10

6

Mea

n tim

e of

con

tact

S5-

S4

(s)

2

-2

PBS CREBS-ODN

CREBAS-ODN

PBS CREBS-ODN

CREBAS-ODN

DONDO

DONDO

Figure 1  (A) Apparatus and behavioral procedure of the object displacement task. The task consists of five sessions. In the first session,

the open field is empty; in sessions 2 through 4, five different objects are placed in the arena in a constant configuration; in session 5, two

of the objects are displaced (DO), thereby changing the spatial configuration of the objects in the open field. A striped pattern is present

on the walls of the open field, and several distal cues (not depicted) surround the apparatus. (B) Effects of intra-NAc administrations of

vehicle, sense (S)-oligonucleotide (ODN) and antisense (AS)-ODN targeted against cAMP response element-binding protein (CREB) on long-

term (left) and short-term (right) spatial memory. To assess the effect of CREB AS-ODN on long-term memory, mice were tested for spatial

discrimination 24 h after training. In the short-term memory procedure, mice were exposed to the spatial change immediately after the last

training session. Mice were always administered intra-NAc 18 h before training. The bars represent mean exploration time of DO and non-

displaced objects (NDO), expressed as the difference between the time spent exploring each object category before and after the spatial

displacement. * p  < 0.05, DO vs. NDO in the same experimental group (modified with permission from Ferretti et al., 2010).

10   A. Rinaldi et al.: Spatial memory and nucleus accumbens

questions regarding the functional relationship between

medial temporal lobe structures and the NAc in spatial

learning and memory consolidation. The requirement

of serial transmission of spatial information between

the hippocampus and the ventral striatum was proved

in two separate studies, using a procedure that allows

a functional disconnection between the two structures

(Floresco et al., 1997; Ito et al., 2008). These results, in par-

allel with electrophysiological observations demonstrat-

ing increased post-training cross-structural firing pattern

correlations for pairs of neurons in the hippocampus and

in the NAc (Lansink et al., 2009), suggest that the cross-

talk between the two structures occurs after training and

might be needed for memory storage. Moreover, in light of

available evidence that the hippocampal formation might

play a temporary role in information storage (Frankland

and Bontempi, 2005), it would be interesting to under-

stand whether information storage in the NAc follows a

dynamic similar to that described for the hippocampus.

The final question raised by these studies is how to

classify the NAc or, more generally, the ventral striatum,

in the framework of the traditional dichotomy between

declarative (explicit) and procedural (implicit) memory

systems (Milner et al., 1998). Declarative memory refers to

the ability of consciously recalling events from the past,

and it is based on the activity of the hippocampus and

adjacent structures. Procedural memory refers to motor

and procedural skills that come to be executed automati-

cally and unconsciously and depends on cortical-basal

ganglia loops (Squire and Zola, 1996; Packard and Knowl-

ton, 2002). Psychologically speaking, spatial memory can

be regarded as declarative, thus implying the classifica-

tion of the ventral striatum in the declarative memory

system. The impairments induced by NAc manipulations

on object recognition (Sargolini et al., 2003b) suggest that

not only contextual but also object information is con-

veyed to the NAc, thus expanding the role of this struc-

ture to different types of declarative memory. It should be

noted that lesions or drug administrations in the ventral

striatum exert behavioral effects in learning and memory

tasks that are very similar to those induced by manipu-

lations of upstream structures, making it difficult to dis-

tinguish the specific contributions of the different compo-

nents of the circuit. Electrophysiological recordings of the

activity of NAc MSNs during different tasks demonstrate

significant firing rate changes in correlation with posi-

tion and movement (Lavoie and Mizumori, 1994; Shibata

et al., 2001; Mulder et al., 2004) as well as reward (Lavoie

and Mizumori, 1994; Lansink et al., 2008). The involve-

ment of NAc neurons in generating motivational signals

and encoding multiple correlates of different types (i.e.,

reward and position) (Lavoie and Mizumori, 1994) sup-

ports the hypothesis that the NAc might be included in

a third system with more integrative functions, such as

invigorating or disinhibiting goal-directed behaviors

(Pennartz et al., 2011).

Acknowledgements: The authors would like to thank

Angelo Grasso for his graphic assistance. This research

was supported by P.R.I.N. grants from M.I.U.R. (to A.O. and

A.M.), DCMC and SaC from A.S.I. (to A.O. and A.M.) and

funding from the Sapienza University (to A.O. and A.M.).

Received June 17, 2012; accepted September 5, 2012

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Alberto Oliverio’s main interests are actions of drugs on behavior,

behavior genetics and pharmacogenetics. During different visits

in Sweden, France and the USA he has refined behavior genetic

approaches and concentrated on different models of learning and

memory. In the most recent years his research deals with the role

of cortical and subcortical structures on motivation and learning.

Author or co-author of about 400 publications, AO is also author

of about 30 chapters in edited books or general reviews in annual

reviews.

Andrea Mele’s research interests are the molecular and neuroanato-

mical bases of learning and memory. During his post-doctoral train-

ing at the NIH he worked with Agu Pert’s and his research focused

on the neurobiology of drug abuse. More recently he has been

interested in the role of subcortical structures in complex forms

of learning investigating the role of the striatal complex in spatial

memory. He has authored many publications on the topic.

Arianna Rinaldi has recently joined the Department of Biology and

Biotechnology at Sapienza University of Rome, after spending many

years as a postdoc in the laboratory of Dr. Matt Nolan at the

University of Edinburgh. She is interested in understanding the

mechanisms of memory encoding and storage in neural circuits,

using a broad variety of approaches, ranging from molecular and

imaging techniques to in vitro electrophysiology and behavioral

analysis.