Reward representations and reward-related learning in the human brain: insights from neuroimaging

This review outlines recent findings from human neuroimaging concerning the role of a highly interconnected network of brain areas including orbital and medial prefrontal cortex, amygdala, striatum and dopaminergic mid-brain in reward processing. Distinct reward-related functions can be attributed to different components of this network. Orbitofrontal cortex is involved in coding stimulus reward value and in concert with the amygdala and ventral striatum is implicated in representing predicted future reward. Such representations can be used to guide action selection for reward, a process that depends, at least in part, on orbital and medial prefrontal cortex as well as dorsal striatum.     

Effects of an N-methyl-d-aspartate receptor agonist and its antagonist CPP on the levels of dopamine and serotonin metabolites in rat striatum collected in vivo by using a brain dialysis technique

3-((±)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) is an antagonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In the present study, levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) were measured after intracerebroventricular injection of NMDA, CPP or both in rat striatum using a brain dialysis method. The injection of NMDA produced a significant increase in DOPAC level. HVA level was also increased by NMDA injection. The level of 5-HIAA was not affected by NMDA injection. The injection of CPP had no effect on DOPAC, HVA and 5-HIAA levels. The injection of CPP restrained the increase of DOPAC and HVA levels induced by NMDA injection. The results suggest that intracerebral injection of NMDA may increase dopamine release from rat striatum, but have no effect on serotonin release. Furthermore, CPP inhibits NMDA induced release of dopamine.     

Phenotypic, maximum genetic, and special environmental variability in prehistoric human populations

The phenotypic variance (V(P)) may be divided into the genetic variance (V(G)), the general environmental variance (V(Eg)), and the special environmental variance (V(Es)). The latter is estimated through repeatability calculation (b). This value is considered the upper limit of heritability and represents maximum genetic variance proportion (V(Gm) = V(G) + V(Eg)) in relation to V(P) (b = (V(G) + V(Eg))/V(P)). This process allows an improved determination of biological relationships among groups from estimators maximizing the genetic information of quantitative characters. Two hundred and thirty-seven individuals inhabiting the northern coast of Chile for 4,000 years were taken as a sample. Measurement was made of six metric characters at both sides of the cranium. Special environmental values (es) were obtained by regression. The difference between these values and the phenotypic values (p) consists in the genetic values plus the general environmental values (g + eg). A mean b value of 0.83 indicated that V(Es) represents 17% of V(P). The results showed: 1) high stability of the maximum genetic variance in time and space, 2) high correlation between the biological relationships model, the phenotypic model, and the maximum genetic model, and 3) random distribution of the nongenetic variation, as expected from the quantitative genetics theory. These results support the use of phenotypic data for the interpretation of the evolution history of prehistoric populations.     

Good riddance to dopamine: Roles for the dopamine transporter in synaptic function and dopamine-associated brain disorders

The neurotransmitter dopamine (DA) plays a critical role in CNS circuits that provide for attention, executive function, reward responses, motivation and movement. DA is inactivated by the cocaine- and amphetamine-sensitive DA transporter (DAT), a protein that also provides a pathway for non-vesicular DA release. After a brief review of DAT function and psychostimulant actions, we consider the importance DAT in relation to the distinct firing patterns of DA neurons that permit awareness of novelty and reward. Finally, we review recent efforts to gather direct support for DAT-linked disorders, with a specific focus on DAT mutations recently identified in subjects with ADHD.     

Robustness of post-reconstruction and direct kinetic parameter estimates under rigid head motion in dynamic brain PET imaging

ObjectiveDynamic PET imaging is extensively used in brain imaging to estimate parametric maps. Inter-frame motion can substantially disrupt the voxel-wise time-activity curves (TACs), leading to erroneous maps during kinetic modelling. Therefore, it is important to characterize the robustness of kinetic parameters under various motion and kinetic model related factors.MethodsFully 4D brain simulations ([¹⁵O]H₂O and [¹⁸F]FDG dynamic datasets) were performed using a variety of clinically observed motion patterns. Increasing levels of head motion were investigated as well as varying temporal frames of motion initiation. Kinetic parameter estimation was performed using both post-reconstruction kinetic analysis and direct 4D image reconstruction to assess bias from inter-frame emission blurring and emission/attenuation mismatch.ResultsKinetic parameter bias heavily depends on the time point of motion initiation. Motion initiated towards the end of the scan results in the most biased parameters. For the [¹⁸F]FDG data, k₄ is the more sensitive parameter to positional changes, while K₁ and blood volume were proven to be relatively robust to motion. Direct 4D image reconstruction appeared more sensitive to changes in TACs due to motion, with parameter bias spatially propagating and depending on the level of motion.ConclusionKinetic parameter bias highly depends upon the time frame at which motion occurred, with late frame motion-induced TAC discontinuities resulting in the least accurate parameters. This is of importance during prolonged data acquisition as is often the case in neuro-receptor imaging studies. In the absence of a motion correction, use of TOF information within 4D image reconstruction could limit the error propagation.     

In vivo functional brain imaging and a therapeutic trial of l-arginine in MELAS patients

Background

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common type of mitochondrial disease and is characterized by stroke-like episodes (SEs), myopathy, lactic acidosis, diabetes mellitus, hearing-loss and cardiomyopathy. The causal hypotheses for SEs in MELAS presented to date are angiopathy, cytopathy and neuronal hyperexcitability. L-arginine (Arg) has been applied for the therapy in MELAS patients.

Scope of review

We will introduce novel in vivo functional brain imaging techniques such as MRI and PET, and discuss the pathogenesis of SEs in MELAS patients. We will further describe here our clinical experience with L-arg therapy and discuss the dual pharmaceutical effects of this drug on MELAS.

Major conclusions

Administration of L-arg to MELAS patients has been successful in reducing neurological symptoms due to acute strokes and preventing recurrences of SEs in the chronic phase. L-Arg has dual pharmaceutical effects on both angiopathy and cytopathy in MELAS.

General significance

In vivo functional brain imaging promotes a better understanding of the pathogenesis and potential therapies for MELAS patients. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.     

Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate

The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [¹¹C]1–4 was achieved by alkylation of their corresponding desmethyl precursors with [¹¹C]CH₃I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [¹¹C]1 and [¹¹C]2 had high striatal accumulation (at peak time) for [¹¹C]1 and [¹¹C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [¹¹C]1 and [¹¹C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [¹¹C]1 and [¹¹C]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [¹¹C]1 reached 1.8 at 30 min with a 3.5-fold striatum:cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [¹¹C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [¹¹C]1 is a promising candidate for quantification of PDE10A in vivo using PET.     

Interplay between aggression,brain monoamines and fur color mutation in the American mink

Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (?2.06 ± 0.03) and tame (+3.5 ± 0.1) populations of wild‐type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive (?1.2 ± 0.1) and tame (+3.0 ± 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (?2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5‐hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks.     

The effect of psychosis associated CACNA1C,and its epistasis with ZNF804A,on brain function

CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)—to better understand how they might induce risk. We recently reported effects on functional VF‐related (for ZNF804A‐rs1344706) and structural (for both) connectivity. We genotyped and fMRI‐scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C‐rs1006737, and its interaction with ZNF804A‐rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions—PPI). Using public data, we reported effects of CACNA1C‐rs1006737 and diagnosis on brain expression. The CACNA1C‐rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto‐temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up‐regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole‐brain, voxel‐wise, and familywise‐error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis—which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.     

Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699

Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT₄ receptors (K_i of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [¹⁸F]MNI-698 and [¹⁸F]MNI-699 were consistent with the known densities of 5-HT₄ in brain. [¹⁸F]MNI-698 and [¹⁸F]MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT₄ receptors in vivo and are currently under preclinical investigation in primates for future human use.     

Quantitative positron emission tomography of mGluR5 in rat brain with [18F]PSS232 at minimal invasiveness and reduced model complexity

Imaging the density of metabotropic glutamate receptor 5 (mGluR5) in brain by positron emission tomography (PET) is of interest in relation to several brain disorders. We have recently introduced [¹⁸F]PSS232, an F‐18‐labeled analog of the mGluR5‐targeting [¹¹C]ABP688. Quantitative PET requires kinetic modeling with an input function (IF) or an appropriate reference tissue model. We aimed at minimizing invasiveness of IF recording in rat and employing this protocol for mGluR5 quantitative PET with [¹⁸F]PSS232. We further aimed at defining models of low complexity for quantitative PET with [¹⁸F]PSS232. The IF was recorded in an arterio‐venous shunt applied by minimally invasive cannulation. PET data were analyzed with a modified two‐tissue compartment model including a single variable for radiometabolite correction in brain. We further evaluated a simple reference tissue model. Receptor‐dependent accumulation was similar to [¹¹C]ABP688 at lower unspecific accumulation of unchanged [¹⁸F]PSS232, in agreement with its higher plasma protein binding and lower lipophilicity. The minimally invasive protocol revealed similar results as the invasive shunt method and parameters calculated with the modified two‐tissue compartment model were similar to those calculated with the standard model. The simple area under the curve ratios agreed with the Logan reference method. [¹⁸F]PSS232 is a promising radioligand for mGluR5 quantification.

     

Physiological variation in estradiol and brain function: a functional magnetic resonance imaging study of verbal memory across the follicular phase of the menstrual cycle

Women frequently complain of memory problems at times in their reproductive lives that are associated with changes in estrogen concentration (e.g. around menopause and childbirth). Further, behavioural studies suggest that memory performance may fluctuate across the menstrual cycle. For example, performance on verbal tasks has been reported to be greatest during phases associated with high estrogen concentrations whereas the opposite has been reported with visuo-spatial tasks. The biological basis of these reported effects remains poorly understood. However, brain imaging studies into the effects of estrogen therapy in postmenopausal women suggest that estrogen modulates the metabolism and function of brain regions sub-serving memory. Furthermore, we have recently reported that acute suppression of ovarian function in young women (with a Gonadotropin Hormone Releasing Hormone agonist) is associated with decreased activation in left prefrontal cortex, particularly the left inferior frontal gyrus (LIFG), during successful verbal memory encoding. We therefore investigated whether physiological variation in plasma estradiol concentration is associated with differences in activity of the LIFG during successful verbal encoding. We hypothesised that higher plasma concentrations of estradiol would be associated with increased brain activity at the LIFG and improved recall performance. Although we did not find a significant relationship between plasma estradiol concentration and verbal recall performance, we report a positive correlation between brain function and estradiol concentration at the LIFG.     

Differential intolerance to loss of function and missense mutations in genes that encode human matricellular proteins

Targeted gene disruption in mice has provided valuable insights into the functions of matricellular proteins. Apart from missense and loss of function mutations that have been associated with inherited diseases, however, their functions in humans remain unclear. The availability of deep exome sequencing data from over 140,000 individuals in the Genome Aggregation Database provided an opportunity to examine intolerance to loss of function and missense mutations in human matricellular genes. The probability of loss-of-function intolerance (pLI) differed widely within members of the thrombospondin, CYR61/CTGF/NOV (CCN), tenascin, small integrin-binding ligand N-linked glycoproteins (SIBLING), and secreted protein, acidic and rich in cysteine (SPARC) gene families. Notably, pLI values in humans had limited correlation with viability of the corresponding homozygous null mice. Among the thrombospondins, only THBS1 was highly loss-intolerant (pLI = 1). In contrast, Thbs1 is not essential for viability in mice. Several known thrombospondin-1 receptors were similarly loss-intolerant, although thrombospondin-1 is not the exclusive ligand for some of these receptors. The frequencies of missense mutations in THBS1 and the gene encoding its signaling receptor CD47 indicated conservation of some residues implicated in specific receptor binding. Deficits in missense mutations were also observed for other thrombospondin genes and for SPARC, SPOCK1, SPOCK2, TNR, and DSPP. The intolerance of THBS1 to loss of function in humans and elevated pLI values for THBS2, SPARC, SPOCK1, TNR, and CCN1 support important functions for these matricellular protein genes in humans, some of which may relate to functions in reproduction or responding to environmental stresses.     

Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European‐Americans (EA; 2927 cases) and 3132 African‐Americans (AA: 1315 cases) participating in the family‐based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h ² in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome‐wide significant (GWS; P < 5E‐08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion‐deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans‐ancestral meta‐analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward‐related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non‐European samples with distinct patterns of substance use may lead to the identification of novel ancestry‐specific genetic markers of risk.     

Decreased dopamine D2 receptor function in cerebral cortex and brain stem: their role in hepatic ALDH regulation in ethanol treated rats

Ethanol exerts numerous pharmacological effects through its interaction with various neurotransmitters. The dopaminergic pathway is associated with cognitive, endocrine, and motor functions, and reinforcement of addictive substances or behaviours. Aldehyde dehydrogenase (ALDH) is a vital enzyme involved with alcohol metabolism and detoxification. In the present study, we investigated the role of cerebral cortex and brain stem dopamine D₂ receptors in the functional regulation on ALDH enzyme activity, in ethanol administrated rats. Two groups of rats were selected viz. control and alcoholic. Cerebral cortex, brain stem and the liver dopamine content was decreased significantly (P < 0.05, 0.05, 0.001, respectively) and homovanillic acid/dopamine (HVA/DA) ratio has significantly increased (P < 0.05, 0.001 and 0.001), respectively in ethanol treated rats when compared to control. Scatchard analysis of [³H]YM-09151-2 binding to synaptic membrane preparations of cerebral cortex and brain stem showed a significant decrease (P < 0.001, 0.05, respectively) in B _max in ethanol treated rats compared to control and the K _d also decreased significantly (P < 0.05). The ALDH analysis showed a significant increase (P < 0.05) in V _max in cerebral cortex, plasma and liver of experimental rats when compared with control without having significant change in brain stem but with decreased K _m (P < 0.001). Our results suggest that decreased function of dopamine mediated through DA D₂ receptor in the cerebral cortex and brain stem enhanced the brain, plasma and liver ALDH activity in ethanol treated rats. This ALDH regulation has significance to correct alcoholics from addiction due to allergic reaction observed in aldehyde accumulation.