Differential patterns of nucleus accumbens activation during anticipation of monetary and social reward in young and older adults

Recent studies have reported inconsistent results regarding the loss of reward sensitivity in the aging brain. Although such an age effect might be due to a decline of physiological processes, it may also be a consequence of age-related changes in motivational preference for different rewards. Here, we examined whether the age effects on neural correlates of reward anticipation are modulated by the type of expected reward. Functional magnetic resonance images were acquired in 24 older (60–78 years) and 24 young participants (20–28 years) while they performed an incentive delay task offering monetary or social rewards. Anticipation of either reward type recruited brain structures associated with reward, including the nucleus accumbens (NAcc). Region of interest analysis revealed an interaction effect of reward type and age group in the right NAcc: enhanced activation to cues of social reward was detected in the older subsample while enhanced activation to cues of monetary reward was detected in the younger subsample. Our results suggest that neural sensitivity to reward-predicting cues does not generally decrease with age. Rather, neural responses in the NAcc appear to be modulated by the type of reward, presumably reflecting age-related changes in motivational value attributed to different types of reward.     

Electrophysiological identification of mesencephalic ventromedial tegmental (VMT) neurons projecting to the frontal cortex, septum and nucleus accumbens

The electrophysiological properties of neurons located in the mesencephalic ventromedial tegmentum (VMT) and the organization of the efferents of these neurons to the frontal cortex, the septum, the nucleus accumbens and the head of the striatum were studied in ketamine-anesthetized rats. The projections of the VMT cells were determined through use of the antidromic activation method. Our results show that VMT projections to different target areas originate mainly from different VMT neurons. However, in some cases single VMT neurons were found to send axon collaterals to two different areas. Three branching patterns were observed: septum-cortex, septum--nucleus accumbens and septum--striatum. The occasional observation of temporally distinct antodromic responses from a single area was considered to result from activation of different branches of the arborizing axon. The distribution of antidromic response latencies for VMT projections to each structure is discussed in relation to the question of dopaminergic versus non-dopaminergic mesolimbic and mesocortical systems.     

Opposite changes in dopamine utilization in the nucleus accumbens and the frontal cortex after electrolytic lesion of the median raphe in the rat

As revealed by the changes in dihydroxyphenylacetic acid (DOPAC) levels and in the DOPAC/Dopamine (DA) ratio, DA utilization was markedly enhanced in the nucleus accumbens and reduced in the prefrontal cortex of rats five days after the electrolytic lesion of the median raphe. These opposite effects were not seen any more seventeen days after the lesion. These results suggest that neurones originating from the median raphe and projecting to the ventral tegmental area exert an opposite effect on the activity of DA cells innervating the nucleus accumbens and on those projecting to the prefrontal cortex.     

Features of compulsive checking behavior mediated by nucleus accumbens and orbital frontal cortex

The quinpirole sensitization model of obsessive‐compulsive disorder was used to investigate the functional role that brain regions implicated in a neuroanatomical circuit of obsessive‐compulsive disorder may play in compulsive checking behavior. Following repeated injections of saline or quinpirole (0.5 mg/kg, twice per week, ×8 injections) to induce compulsive checking, rats received N‐methyl‐d ‐aspartate lesions of the nucleus accumbens core (NAc), orbital frontal cortex (OFC) and basolateral amygdala, or sham lesions. When retested at 17 days post‐surgery, the results showed effects of NAc and OFC but not basolateral amygdala lesion. NAc lesions affected measures indicative of the amount of checking behavior, whereas OFC lesions affected indices of staying away from checking. The pattern of results suggested that the functional roles of the NAc and OFC in checking behavior are to control the vigor of motor performance and focus on goal‐directed activity, respectively. Furthermore, similarities in behavior between quinpirole sham rats and saline NAc lesion rats suggested that quinpirole may drive the vigor of checking by inhibition of NAc neurons, and that the NAc may be a site for the negative feedback control of checking.     

Dopamine denervation of frontal cortex or nucleus accumbens does not affect ACTH-induced grooming behaviour

Studies with dopamine (DA) receptor antagonists have implicated brain DA systems in the increased grooming behaviour elicited by intracerebroventricular (i.c.v.) administration of ACTH or exposure to a novel environment. To evaluate the potential contributions of DA terminals innervating frontal cortex and nucleus accumbens, stereotaxically guided injections of 6-hydroxydopamine (6-OHDA) were made into these regions of rat brain following peripheral administration of desmethylimipramine and pargyline. Despite an 88% mean reduction of DA, and 68% mean reduction of noradrenaline in frontal cortex, the amount of grooming behaviour observed either in a novel cage, or after i.c.v. injection of ACTH1-24 was not detectably altered. The lesions also did not affect locomotor activity measured during the scoring of grooming, in an open field, in photocell cages, or in a running wheel, even in the animals most severely depleted of DA. Following nucleus accumbens 6-OHDA infusions, depletions of DA as great as 99% were obtained. Animals with accumbens depletions greater than 90% showed the expected attenuation of amphetamine-stimulated locomotor activity. Nevertheless, they exhibited normal grooming scores in a novel cage, and in response to i.c.v. ACTH1-24. It is concluded that dopaminergic terminals in nucleus accumbens and probably those in frontal cortex are not necessary for the expression of novelty- or ACTH-induced grooming.     

Effects of corticotropin-releasing hormone receptor antagonists on cocaine-induced dopamine overflow in the medial prefrontal cortex and nucleus accumbens of rats

Recent evidence suggests an important role for corticotropin-releasing hormone (CRH) and CRH receptors in cocaine reinforcement. CRH receptor antagonists reduce cocaine self-administration and attenuate the reinstatement of extinguished cocaine-seeking behavior, but little is known about the mechanisms involved. One possible mechanism for these effects may involve the cocaine-induced activation of CRH located in brain regions outside of the hypothalamus. CRH has been shown to increase dopaminergic transmission in regions relevant for cocaine reinforcement, such as the medial prefrontal cortex and the nucleus accumbens. Here, we report that CP-154,526, a CRH1-receptor antagonist, actually enhances cocaine-induced increases in dopamine overflow in the medial prefrontal cortex, measured using in vivo microdialysis. In contrast, the receptor antagonist did not alter cocaine-induced increases in dopamine in most of the nucleus accumbens, except for the most rostral part. These data suggest a surprising role for prefrontal cortex dopamine in the ability of CRH-receptor antagonists to attenuate cocaine seeking in rats.     

A projection from the entorhinal cortex to the nucleus accumbens in the rat

A study was performed in which both anterograde ([³H]leucine radioautography) and retrograde (horseradish peroxidase (HRP) histochemistry) tracing methods were employed to identify the origin of the fimbrial projection to the nucleus accumbens in the rat. The data reveal that this pathway arises predominantly from layers II–III of the anterior two-thirds of entorhinal cortex rather than from any part of hippocampal formation.     

Pramipexole modulates the neural network of reward anticipation

Pramipexole is widely prescribed to treat Parkinson's disease. It has been found to cause impulse control disorders such as pathological gambling. To examine how pramipexole modulates the network of reward anticipation, we carried out a pharmacological functional magnetic resonance imaging study with a double-blind, within-subject design. During the anticipation of monetary rewards, pramipexole increased the activity of the nucleus accumbens (NAcc), enhanced the interaction between the NAcc and the anterior insula, but weakened the interaction between the NAcc and the prefrontal cortex. These results suggest that pramipexole may exaggerate incentive and affective responses to possible rewards, but reduce the top-down control of impulses, leading to an increase in impulsive behaviors. This imbalance between the prefrontal-striatum connectivity and the insula-striatum connectivity may represent the neural mechanism of pathological gambling caused by pramipexole.     

Evidence for the existence of a substance P-containing pathway from the nucleus laterodorsalis tegmenti (Castaldi) to the medial frontal cortex of the rat

A long ascending substance P (SP)-containing pathway from the nucleus laterodorsalis tegmenti (TLD) to the medial frontal cortex (MFC) has been demonstrated by means of experimental immunohistochemical procedures. The unilateral destruction of the TLD, which contains numerous SP-like immunoreactive (SPLI) cells, resulted in a marked ipsilateral decrease in the SPLI fibers in the MFC.     

Mesolimbic recruitment by nondrug rewards in detoxified alcoholics: effort anticipation, reward anticipation, and reward delivery

Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol‐dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post‐response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two‐stage presentation of reward‐predictive information, subjects saw cues signaling opportunities to win Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol‐dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post‐response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two‐stage presentation of reward‐predictive information, subjects saw cues signaling opportunities to win Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol-dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post-response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two-stage presentation of reward-predictive information, subjects saw cues signaling opportunities to win $0, $1, or $10 for responding to a target. Following this response, subjects were notified whether their success would be indicated by a lexical notification (“Hit?”) or by delivery of a monetary reward (“Win?”). After a variable interval, subjects then viewed the trial outcome. We found no significant group differences in voxelwise activation by task contrasts, or in signal change extracted from VS. Both ADP and controls showed significant VS and other limbic recruitment by pre-response reward anticipation. In addition, controls also showed VS recruitment by post-response reward-anticipation, and ADP had appreciable subthreshold VS activation. Both groups also showed similar mesolimbic responses to reward deliveries. Across all subjects, a questionnaire measure of “hot” impulsivity correlated with VS recruitment by post-response anticipation of low rewards and with VS recruitment by delivery of low rewards. These findings indicate that incentive-motivational processing of nondrug rewards is substantially maintained in recovering alcoholics, and that reward-elicited VS recruitment correlates more with individual differences in trait impulsivity irrespective of addiction.     

Nucleus accumbens neurons encode predicted and ongoing reward costs in rats

Efficient decision-making requires that animals consider both the benefits and the costs of potential actions, such as the amount of effort or temporal delay involved in reward seeking. The nucleus accumbens (NAc) has been implicated in the ability to choose between options with different costs and overcome high costs when necessary, but it is not clear how NAc processing contributes to this role. Here, neuronal activity in the rat NAc was monitored using multi-neuron electrophysiology during two cost-based decision tasks in which either reward effort or reward delay was manipulated. In each task, distinct visual cues predicted high-value (low effort/immediate) and low-value (high effort/delayed) rewards. After training, animals exhibited a behavioral preference for high-value rewards, yet overcame high costs when necessary to obtain rewards. Electrophysiological analysis indicated that a subgroup of NAc neurons exhibited phasic increases in firing rate during cue presentations. In the effort-based decision task (but not the delay-based task), this population reflected the cost-discounted value of the future response. In contrast, other subgroups of cells were activated during response initiation or reward delivery, but activity did not differ on the basis of reward cost. Finally, another population of cells exhibited sustained changes in firing rate while animals completed high-effort requirements or waited for delayed rewards. These findings are consistent with previous reports that implicate NAc function in reward prediction and behavioral allocation during reward-seeking behavior, and suggest a mechanism by which NAc activity contributes to both cost-based decisions and actual cost expenditure.     

Dendritic morphology of neurons in medial prefrontal cortex,hippocampus, and nucleus accumbens in adult SH rats

We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months old), the dendritic morphological changes of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus and medium spiny neurons of the nucleus accumbens (NAcc) induced by the chronic effect of high‐blood pressure. As control animals, we used Wistar‐Kioto (WK) rats. Blood pressure was measured every 2 months to confirm the increase in arterial blood pressure. Spontaneous locomotor activity was assessed, and then brains were removed to study the dendritic morphology by the Golgi‐Cox stain method followed by Sholl analysis. SH animals at 4 and 8 months of age showed decreased spine density in pyramidal neurons from the mPFC and in medium spiny cells from the NAcc. At 8 months of age as well the pyramidal neurons from the hippocampus exhibited a reduction in the number of dendritic spines. An increase in locomotion in a novel environment at all ages in the SH rats was observed. Our results indicate that high‐blood pressure alters the neuronal dendrite morphology of the mPFC, hippocampus, and NAcc. The increased locomotion behavior supports the idea that dopaminergic transmission is altered in the SH rats. This could enhance our understanding of the consequences of chronic high‐blood pressure on brain structure, which may implicate cognitive impairment in hypertensive patients. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Dissociation of prefrontal cortex and nucleus accumbens dopaminergic systems in conditional learning in rats

There is converging evidence that the prefrontal and mesolimbic dopaminergic (DAergic) systems are involved in the performance of a variety of tasks that require the use of contextual, or task-setting, information to select an appropriate response from a number of candidate responses. Performance on tasks of this nature are impaired in schizophrenia and in rats exposed to psychotomimetics; impairments that are often attenuated by administration of dopamine (DA) antagonists. Rats were trained on either a complex instrumental discrimination task, that required the use of task-setting cues, or a simple discrimination task that did not. Following training, microdialysis probes were implanted unilaterally in either the medial prefrontal cortex (mPFC) or nucleus accumbens (NAc) and samples were collected in freely moving animals during a behavioural test session. In Experiment 1, we found no difference in levels of DA in the mPFC of rats while they were performing the two discrimination tasks. Rats that performed the complex task did, however, show significantly higher mPFC DA levels relative to rats in the simple discrimination condition following the end of the behavioural test session. In Experiment 2, rats performing the conditional discrimination showed lower levels of DA in the NAc compared to the simple discrimination group both during the test session and after it. These results provide direct evidence that conditional discrimination tasks engage frontal and mesolimbic DAergic systems and are consistent with the proposal that regulation of fronto-striatal DA is involved in aspects of cognitive control that are known to be impaired in individuals with schizophrenia.     

THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction

Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using Δ⁹-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction.     

Topographic organization of efferent projections of medial frontal cortex

By using fluorescent retrograde tracers, we compared efferent projections of the medial frontal cortex to two subcortical areas: the superior colliculus, a somatic motor area, and the laterodorsal tegmental nucleus, a visceral motor area. Neurons projecting to the superior colliculus originated in layer V of the cingulate (Cg1 area) and medial agranular cortex, while neurons projecting to the laterodorsal tegmental nucleus originated in layers V and VI of the cingulate (Cg3 area) and infralimbic cortex. Thus, within the medial frontal cortex, the ventral portion (the Cg3 and infralimbic areas) may be a visceral motor area while the dorsal portion is a somatic motor region.     

Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens

The prefrontal cortex and nucleus accumbens are primary recipients of medial thalamic inputs, prominently including projections from the thalamic paraventricular nucleus. It is not known if paraventricular neurons collateralize to innervate both the prefrontal cortex and nucleus accumbens. We used dual retrograde tract tracing methods to examine this question. A small population of paraventricular neurons was found to innervate the prefrontal cortex and medial nucleus accumbens. These data suggest that the thalamic paraventricular nucleus may coordinately influence activity in the prefrontal cortex and ventral striatum.     

Dissociating medial frontal and posterior cingulate activity during self-reflection

Motivationally significant agendas guide perception, thoughtand behaviour, helping one to define a ‘self’ andto regulate interactions with the environment. To investigateneural correlates of thinking about such agendas, we asked participantsto think about their hopes and aspirations (promotion focus)or their duties and obligations (prevention focus) during functionalmagnetic resonance imaging and compared these self-reflectionconditions with a distraction condition in which participantsthought about non-self-relevant items. Self-reflection resultedin greater activity than distraction in dorsomedial frontal/anteriorcingulate cortex and posterior cingulate cortex/precuneus, consistentwith previous findings of activity in these areas during self-relevantthought. For additional medial areas, we report new evidenceof a double dissociation of function between medial prefrontal/anteriorcingulate cortex, which showed relatively greater activity tothinking about hopes and aspirations, and posterior cingulatecortex/precuneus, which showed relatively greater activity tothinking about duties and obligations. One possibility is thatactivity in medial prefrontal cortex is associated with instrumentalor agentic self-reflection, whereas posterior medial cortexis associated with experiential self-reflection. Another, notnecessarily mutually exclusive, possibility is that medial prefrontalcortex is associated with a more inward-directed focus, whileposterior cingulate is associated with a more outward-directed,social or contextual focus.     

Brain stimulation reward and dopamine terminal fields. I. Caudate-putamen, nucleus accumbens and amygdala

The boundaries and relative sensitivity of brain stimulation reward were mapped in relation to the dopamine (DA) terminal fields of the striatum and adjacent limbic structures. Brain stimulation was rewarding throughout the caudate and nucleus accumbens and in portions of the amygdala and olfactory tubercle. The best striatal sites were anterior, ventral and medial; this correlated with an anterior-posterior gradient but not with a dorsal-ventral or a medial-lateral gradient of DA terminal density. No close correspondence was seen between the boundaries of the reward system and those of the DA terminal fields as revealed by glyoxylic acid-induced DA fluorescence. Reward sites in the olfactory tubercle and amygdala were found in DA-free as well as DA-rich regions of these structures; stimulation in DA-rich regions did not always support self-stimulation. These data go against the view that direct activation of dopamine terminals or their efferent targets accounts for the rewarding quality of stimulation in these regions.     

Posterior medial frontal cortex and threat-enhanced religious belief: a replication and extension

Research indicates that the posterior medial frontal cortex (pMFC) functions as a ‘neural alarm’ complex broadly involved in registering threats and helping to muster relevant responses. Holbrook and colleagues investigated whether pMFC similarly mediates ideological threat responses, finding that downregulating pMFC via transcranial magnetic stimulation (TMS) caused (i) less avowed religious belief despite being reminded of death and (ii) less group bias despite encountering a sharp critique of the national in-group. While suggestive, these findings were limited by the absence of a non-threat comparison condition and reliance on sham rather than control TMS. Here, in a pre-registered replication and extension, we downregulated pMFC or a control region (MT/V5) and then primed participants with either a reminder of death or a threat-neutral topic. As mentioned previously, participants reminded of death reported less religious belief when pMFC was downregulated. No such effect of pMFC downregulation was observed in the neutral condition, consistent with construing pMFC as monitoring for salient threats (e.g. death) and helping to recruit ideological responses (e.g. enhanced religious belief). However, no effect of downregulating pMFC on group bias was observed, possibly due to reliance on a collegiate in-group framing rather than a national framing as in the prior study.