Ventral striatal activity links adversity and reward processing in children

Adversity impacts many aspects of psychological and physical development including reward-based learning and decision-making. Mechanisms relating adversity and reward processing in children, however, remain unclear. Here, we show that adversity is associated with potentiated learning from positive outcomes and impulsive decision-making, but unrelated to learning from negative outcomes. We then show via functional magnetic resonance imaging that the link between adversity and reward processing is partially mediated by differences in ventral striatal response to rewards. The findings suggest that early-life adversity is associated with alterations in the brain’s sensitivity to rewards accounting, in part, for the link between adversity and altered reward processing in children.     

Psychosocial problems and recruitment of incentive neurocircuitry: exploring individual differences in healthy adolescents

Maturational differences in brain responsiveness to rewards have been implicated in the increased rates of injury and death in adolescents from behavior-related causes. However, much of this morbidity is related to drug intoxication or other externalizing behaviors, and may be concentrated in a subset of adolescents who are at psychosocial or neurobiological risk. To examine whether individual differences in psychosocial and behavioral symptomatology relate to activation of motivational neurocircuitry, we scanned 26 psychiatrically healthy adolescents using fMRI as they performed a monetary incentive delay task. Overall Problem Density on the Drug Use Screening Inventory (DUSI-OPD) correlated positively with activation of ventral mesofrontal cortex (mFC) during anticipation of responding for rewards (vs responding for no incentive). In addition, DUSI-OPD correlated positively with right ventral striatum recruitment during anticipation of responding to win rewards (vs responding for no incentive or to avoid losses of identical magnitudes). Finally, a psychophysiological interaction (PPI) analysis indicated that increased connectivity between nucleus accumbens and portions of anterior cingulate and mFC as a function of reward prospects also correlated with DUSI-OPD. These findings extend previous reports demonstrating that in adolescents, individual differences in reactivity of motivational neurocircuitry relate to different facets of impulsivity or externalizing behaviors.     

Ventral tegmental area opioid mechanisms and modulation of ingestive behavior

In this paper we report on the effects of intra-VTA infusion of opioid agonists on rat ingestive behavior in a variety of experimental contexts. When the animals were tested outside of their home cages surrounded only by food-pellets (Experiment 1), the injection of the mu-opioid agonist DAMGO, but not the kappa-opioid agonist U-50,488H, into the ventral tegmental area facilitated food-related behaviors, decreasing the latency to feed and increasing the number of interactions with food. When, as in Experiment 2, gnawable objects and a drinking tube were also available, intra-VTA DAMGO gnawing and drinking behaviors, whereas the effects on feeding were negligible. These effects intra-VTA DAMGO increased were greatly enhanced in rats that underwent repeated treatments with amphetamine. On the other hand, when food-related behaviors were studied in a home-cage, where access to the food supply was achieved by entry into a tunnel, latency to feed and total food-intake were not enhanced in tests made during either the dark or the light phase (Experiment 3 and 4). This was true whether powdered standard lab chow or a highly palatable food was available. It appears that when a number of alternative incentive stimuli are available, increases in dopamine transmission such as that induced by intra-VTA DAMGO may ultimately have the effect of interfering with behavior normally directed primarily to one of these stimuli, by enhancing the salience of others. These effects bears some resemblance to the effects of tail-pinch and electrical brain stimulation of the medial forebrain bundle-lateral hypothalamic area on the responses to natural incentive stimuli.     

Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward‐driven behaviors, which can result in life‐altering morbidity. The mesocorticolimbic dopamine network guides reward‐motivated behavior; however, its role in this treatment‐related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward‐learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD‐fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex‐matched PD patients with (n = 19) or without (n = 18) ICB. An incentive‐based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole‐brain voxelwise analyses and region‐of‐interest‐based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala‐to‐midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum‐to‐subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment‐avoidance learning. These data indicate that PD‐ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward‐based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509–521, 2018. © 2017 Wiley Periodicals, Inc.     

Modified Bielschowsky stain and immunohistochemical studies on striatal plaques in Alzheimer's disease

Summary The nature of senile plaques (SP) in the striatum in 14 cases of Alzheimer's disease (AD) was investigated with the modified Bielschowsky stain and immunohistochemistry using antibodies to a amyloid synthetic peptide, ubiquitin, tau protein, and paired helical filaments (PHF). Striatal SP, composed of amyloid deposits with or without neuritic elements, were demonstrated in all AD cases examined. Compact and perivascular amyloid deposits were concentrated in the ventral striatum, including the nucleus accumbens. Many diffuse amyloid deposis in the ventral striatum contained ubiquitin-positive granular elements, presumably representing dystrophic neurites, whereas most of those in the dorsal striatum did not have such elements. On the other hand, most compact amyloid deposits in both ventral and dorsal striatum had ubiquitin immunoreactivity. Dystrophic neurites with tau or PHF immunoreactivity were detected particularly around compact amyloid deposits. Our results indicate that the ventral striatum, which is closely affiliated with the limbic system, is frequently affected by amyloid deposits with dystrophic neurites, and suggest that the ventral striatum is particularly vulnerable to AD. Furthermore, our results suggest that amyloid deposits, especially compact deposits, may induce dystrophic neurites.Supported by NIH grant: AG06803 and AG4145     

Sexual motivation: involvement of endogenous opioids in the ventral tegmental area

The sexual motivation and performance of male rats were observed in a bilevel testing chamber after bilateral infusion of 40 pmol β-endorphin, 2.75 nmol naloxone or saline into the ventral tegmental area for four succeeding, weekly tests. In the 5 min prior to introduction of the female rat, the male rat explores the bilevel testing chamber. It was previously shown that the increase over tests of these anticipatory level changes is sexually motivated and a response to olfactory stimuli. Naloxone infusion into the VTA prevented the increase of anticipatory level changes. β-Endorphin failed to affect the anticipatory level-changing behavior. The sexual performance was unaffected by naloxone or β-endorphin treatment, but the number of ejaculating rats decreased with repeated testing after naloxone treatment. It is concluded that endogenous opioid systems in the ventral tegmental area contribute to the stimulation of sexual motivation and/or reward, presumably by stimulating the mesolimbic dopamine system in response to sex-related olfactory stimuli.     

Differential effects of kainic acid on dopamine and serotonin metabolism in ventral and dorsal striatal regions

The comparative effects of kainic acid (KA) on dopamine (DA) and serotonin (5-HT) metabolism in ventral and dorsal striatum were investigated. Local injection of KA into the caudate-putamen (CP) increased by 155% DOPAC (2,3-dihydrophenylacetic acid), by 114% HVA (homovanillic acid) and by 79% 5-HIAA (5-hydroxyindoleacetic acid) concentrations: with little or no effect on monoamine levels. The (DOPAC + HVA)/DA ratio increased from 0.33 ± 0.2 in vehicle-treated to 0.77 ± 0.1 in KA-treated CP. 5-HIAA/5-HT ratio increased from 2.7 ± 0.2 to 5.9 ± 0.1 after KA treatment. However, direct KA injections into the olfactory tubercle (OT), the most ventral part of the ventral striatum, did not alter significantly the levels of DA, 5-HT, DOPAC, HVA or 5-HIAA. Since KA is a neurotoxin which preferentially destroys perykaria and dendrites, leaving unchanged terminal boutons and axons of passage, the lack of effects on DA and 5-HT metabolism in OT suggests, that contrary to the CP, interneurons and projecting neurons in the OT play no role in inhibitory feedback mechanisms to control DA and 5-HT activities.     

Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study

To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs-suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.     

Feeding induced by microinjections of NMDA and AMPA-kainate receptor antagonists into ventral striatal and ventral pallidal areas of the pigeon

The participation of glutamatergic circuits of the ventral basal ganglia in feeding-related regulatory mechanisms has been extensively indicated in primate and rodent species. In avian species, it has been shown that ICV injections of MK-801 or of CNQX increase food intake and reduce the latency of feeding initiation in free-feeding pigeons. In the present study, the effects of local injections of MK-801 (6 nmol), CNQX (160 nmol) or vehicle (0.2 microl) into a number of ventral striatopallidal nuclei on feeding, drinking and non-ingestive (sleep, preening) spontaneous behaviors were investigated in free-feeding pigeons (Columba livia). Intense feeding responses associated with an increased duration of feeding behavior were consistently recorded after injections of MK-801 or CNQX into the medial two-thirds of the tuberculum olfactorium (TO), the ventral aspect of lobus parolfactorium (LPOv), or the ventral pallidum (VP). In contrast, the latency of feeding initiation was unaffected by these treatments. No changes in drinking, preening or sleep responses were observed after drug injections into the TO/LPOv/VP area. These data indicate that glutamate-mediated circuits in the TO/LPOv/VP area can play an inhibitory role in feeding behavior in this species, contributing to the conclusion of a feeding bout, thus delaying satiation processes, and that these effects may be mediated by AMPA and NMDA receptors. Additionally, our data support the notion that a region functionally and anatomically comparable to the mammalian accumbens shell may be present in the TO/LPOv/VP region of the pigeon, and that the existence of a glutamatergic circuit in the ventral striatum controlling feeding-related phenomena may represent a highly conserved attribute throughout the amniote's evolution.     

Reversal learning in Parkinson's disease depends on medication status and outcome valence

We investigated the role of dopamine in distinct forms of reversal shifting by comparing two groups of patients with mild Parkinson's disease (PD), one ON and one OFF their normal dopaminergic medication. In accordance with our previous work, patients ON medication exhibited impaired reversal shifting relative to patients OFF medication. The present results extend previous studies by showing that the medication-induced deficit on reversal shifting was restricted to conditions where reversals were signaled by unexpected punishment. By contrast, patients ON medication performed as well as patients OFF medication and controls when the reversal was signaled by unexpected reward. The medication-induced deficit was particularly pronounced in patients on the dopamine D3 receptor agonist pramipexole. These data indicate that dopaminergic medication in PD impairs reversal shifting depending on the motivational valence of unexpected outcomes.     

The role of motivation and reward neural systems in vocal communication in songbirds

Many vertebrates are highly motivated to communicate, suggesting that the consequences of communication may be rewarding. Past studies show that dopamine and opioids in the medial preoptic nucleus (mPOA) and ventral tegmental area (VTA) play distinct roles in motivation and reward. In songbirds, multiple lines of recent evidence indicate that the roles of dopamine and opioid activity in mPOA and VTA in male birdsong differ depending upon whether song is used to attract females (sexually-motivated) or is produced spontaneously (undirected). Evidence is reviewed supporting the hypotheses that (1) mPOA and VTA interact to influence the context in which a male sings, (2) distinct patterns of dopamine activity underlie the motivation to produce sexually-motivated and undirected song, (3) sexually-motivated communication is externally reinforced by opioids released as part of social interactions, and (4) undirected communication is facilitated and rewarded by immediate opioid release linked to the act of singing.     

Quantitative assessment of female sexual motivation in the rat: Hormonal control of motivation

While a good deal of information has been garnered in the last few decades regarding the neural and hormonal control of female sexual behavior, literature elucidating these mechanisms with respect to female sexual motivation has been scarce. We believe that one reason for this is the lack of a standardized paradigm that will quantify female sexual motivation while allowing for sexual interaction to occur. Here we describe a two-chambered apparatus that utilizes operant responding (nose poking) to quantify female sexual motivation. During the test, the female exhibits nose pokes to gain access to a sexually active male, with whom she is allowed to mate. Therefore, this apparatus allows for examination of sexual behavior as well as quantification of sexual motivation by assessing the number of nose pokes the female will exhibit within a fixed interval to gain access to the male.We report that hormone priming significantly increases sexual motivation in the female as indicated by the number of nose pokes she will exhibit to gain access to the male. Additionally, hormone primed females enter the male compartment after a shorter period and spend more time in direct contact with the male compared to when they are not hormone primed. In contrast, when females are not hormone primed they spend more time in view, but out of reach, of the male.This paradigm will help to advance the study of female sexual motivation, providing a method for quantifiable assessment of female sexual motivation while allowing for sexual activity to occur.     

Intracellular preoptic and striatal monoamines in pregnant and lactating rats: possible role in maternal behavior

In many mammals, hormonal fluctuations during pregnancy and parturition produce neurochemical events that are necessary for the transition from a non-maternal state to a maternal state that occurs when infants are born. However, the nature of these events is mostly unknown. We investigated whether changes in dopamine (DA) and serotonin (5-HT) activity within the preoptic area (POA) and striatum, neural sites important for some maternal behaviors, could be part of this process. Female rats were sacrificed as either diestrus virgins, on pregnancy day 10 or 20, on the day of parturition, or on day 7 or 17 of lactation. Bilateral tissue punches from the POA, dorsolateral striatum (ST_dl), and nucleus accumbens (NA) were obtained and levels of intracellular DA and 5-HT analyzed with high-performance liquid chromatography with electrochemical detection (HPLC–EC). In the POA, DA was high in virgins and during early pregnancy, lowest on the day of parturition, and very high during lactation. Although there were no changes in the DOPAC to DA ratio (i.e., turnover), DOPAC levels also followed this pattern. 5-HT turnover in the POA was lower in virgins compared to other groups. In the ST_dl, DA turnover was highest during late pregnancy and on the day of parturition, while no changes in 5-HT measures were found. No significant effects were found in the NA. Therefore, decreased DAergic activity in the POA and increased DAergic activity in the ST_dl occurs around parturition, the time when maternal behavior emerges, and may influence its onset.     

Aversive disinhibition of behavior and striatal signaling in social avoidance

Social avoidance is a major factor contributing to the development and maintenance of anxiety and depressive symptoms. Converging evidence suggests that social avoidance is associated with abnormal aversive processing and hyperactive amygdala signaling. However, what are the consequences of such abnormal aversive processing for action and for the neural mechanisms implementing action is unclear. Existing literature is conflicting, pointing at either enhanced or reduced action inhibition. We investigated the interaction between aversion and action in social avoidance by comparing the effects of aversive vs appetitive faces on a go/no-go task and associated striatal signals in 42 high and low socially avoidant individuals. We combined fMRI with a novel probabilistic learning task, in which emotional valence (angry and happy faces) and optimal response (go- and no-go-responses) were manipulated independently. High compared with low socially avoidant individuals showed reduced behavioral inhibition (proportion no-go-responses) for angry relative to happy faces. This behavioral disinhibition correlated with greater striatal signal during no-go-responses for angry relative to happy faces. The results suggest that social avoidant coping style is accompanied by disinhibition of action and striatal signal in the context of social threat. The findings concur with recent theorizing about aversive disinhibition and affective disorders.     

Evidence that the nucleus accumbens shell, ventral pallidum, and lateral hypothalamus are components of a lateralized feeding circuit

Pronounced feeding can be elicited by injections of the GABA_A agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh). This region of AcbSh has been shown to project to both the lateral hypothalamus (LH) and the medial ventral pallidum (VPm). The current study examined the effects of unilateral LH or VPm lesions on the ingestive responses induced by injections of muscimol into the AcbSh on either the same or the opposite side of the brain. We found that lesions of either of these structures drastically attenuated feeding induced from the ipsilateral, as compared to the contralateral, AcbSh. The “ipsilateral/contralateral disruption design” employed here virtually rules out the possibility that the suppressive effects of the lesions were nonspecific and suggests that the VPm and LH play essential roles in mediating the ingestive effects of inactivation of the AcbSh.     

Neuropharmacology of the nucleus accumbens: Iontophoretic applications of morphine and nicotine have contrasting effects on single-unit responses evoked by ventral pallidal and fimbria stimulation

Extracellular recordings within the nucleus accumbens (NAS) of halothane anesthetized rats have revealed that iontophoretically applied morphine and nicotine have contrasting effects on neuronal responses evoked by fimbria or VP stimulation. Iontophoretically applied morphine inhibited NAS single-unit responses evoked by VP stimulation but did not affect unit responses evoked by fimbria stimulation. In contrast, iontophoretically applied nicotine had no effect on NAS single-unit responses evoked by VP stimulation but inhibited single-unit responses evoked by fimbria stimulation. Spontaneously active NAS units were inhibited by iontophoretically applied morphine but were unaffected by nicotine. In addition, experiments were conducted to determine whether NAS unit responses to electrical stimulation of the VP were likely to involve cell body as opposed to axonal activations. Selective cell body stimulation by glutamate microinfusions into the VP region excited spontaneously active VP single-units. Concurrently recorded NAS unit responses to electrical stimulation of the VP were also excited. These results are consistent with the idea that NAS evoked responses to VP electrical stimulation involve somal activation. Generally, these results suggest a specific neuropharmacological organization of the NAS. Analysis of the effects of morphine and nicotine on other NAS circuits will establish a systems level understanding of NAS responses to reinforcers. © 1995 Wiley-Liss, Inc.     

Prefrontal and striatal activation during sequence learning in geriatric depression.

BACKGROUND: Frontostriatal dysfunction is a primary hypothesis for the neurocognitive changes of depression in late life. The aim of the present study was to test this hypothesis with the use of functional magnetic resonance imaging (fMRI) tasks that are known to engage the prefrontal and neostriatal cognitive circuits. METHODS: Twenty-three elderly subjects (mean age, 69.9 years) participated: 11 subjects with a current major depressive episode and 12 nondepressed elderly control subjects. Subjects underwent fMRI while performing a concurrent implicit and explicit sequence learning task. Region of interest (ROI)-based analyses were conducted, focusing on the dorsal anterior cingulate cortex, the dorsolateral prefrontal cortex, and the neostriatum. RESULTS: As expected, both the control and depressed subjects learned the sequence during both implicit and explicit conditions. During explicit learning, decreased prefrontal activation was found in the depressed subjects, along with increased striatal activation. The increased striatal activity in the depressed subjects was due to increased activity on the trials that violated the sequence. During implicit learning, no significant differences were found between the groups in the identified ROIs. CONCLUSIONS: The increased striatal activation on trials that violated the sequence demonstrates a greater response to negative feedback for depressed compared with control subjects. Our observations of significant differences in both prefrontal and striatal regions in the depressed elderly subjects relative to elderly control subjects supports the frontostriatal dysfunction hypothesis of late-life depression.