Substantia Nigra Ventral Tegmental Area Research Articles

The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance

Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra–ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.

Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers.

While variations in the first intron of the fat mass and obesity-associated gene (FTO, rs9939609 T/A variant) have long been identified as a major contributor to polygenic obesity, the mechanisms underlying weight gain in risk allele carriers still remain elusive. On a behavioral level, FTO variants have been robustly linked to trait impulsivity. The regulation of dopaminergic signaling in the meso-striatal neurocircuitry by these FTO variants might represent one mechanism for this behavioral alteration. Notably, recent evidence indicates that variants of FTO also modulate several genes involved in cell proliferation and neuronal development. Hence, FTO polymorphisms might establish a predisposition to heightened trait impulsivity during neurodevelopment by altering structural meso-striatal connectivity. We here explored whether the greater impulsivity of FTO variant carriers was mediated by structural differences in the connectivity between the dopaminergic midbrain and the ventral striatum. Eighty-seven healthy normal-weight volunteers participated in the study; 42 FTO risk allele carriers (rs9939609 T/A variant, FTO + group: AT, AA) and 39 non-carriers (FTO - group: TT) were matched for age, sex and body mass index (BMI). Trait impulsivity was assessed via the Barratt Impulsiveness Scale (BIS-11) and structural connectivity between the ventral tegmental area/substantia nigra (VTA/SN) and the nucleus accumbens (NAc) was measured via diffusion weighted MRI and probabilistic tractography. We found that FTO risk allele carriers compared to non-carriers, demonstrated greater motor impulsivity (p = 0.04) and increased structural connectivity between VTA/SN and the NAc (p< 0.05). Increased connectivity partially mediated the effect of FTO genetic status on motor impulsivity. We report altered structural connectivity as one mechanism by which FTO variants contribute to increased impulsivity, indicating that FTO variants may exert their effect on obesity-promoting behavioral traits at least partially through neuroplastic alterations in humans.

Substantia nigra integrity is associated with poorer recognition memory for novel stimuli in early Alzheimer’s disease

AbstractBackgroundThe substantia nigra/ventral tegmental area (SN/VTA), the brain’s most prominent dopamine source, is involved in novelty exploration and episodic memory. Using a novelty detection task combined with neuromelanin‐sensitive MRI, this work aimed to investigate the relationship between SN integrity, neural novelty response and subsequent recognition memory performance in individuals with early Alzheimer’s disease.Method79 healthy subjects, 54 participants with subjective cognitive decline (SCD), 18 with mild cognitive impairment (MCI), and 10 individuals with ADD from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study performed a previously published scene novelty and encoding task (“FADE”) using 3T fMRI. Additional 3D T1‐weighted FLASH images were collected to visualize and quantify the volume and MRI contrast in the SN.Linear regression models were generated to assess for associations between either SN volume and median MRI contrast, considered as proxy integrity measures, with functional activity during novelty and subsequent recognition memory performance (dprime). We used site, gender, age and years of education as covariates. We assessed AD pathology in a subsample of individuals with CSF biomarkers (n = 71).ResultWe observed a significant decline in SN volume (p = 0.003) but not MRI contrast in ADD compared to healthy controls. The SN volume in the whole sample correlated positively with recognition memory for novel stimuli (r = 0.35; p = 0.02,). This association held in the CSF subsample (r = 0.31; p = 0.034) and also after correcting for levels of both tau (phosphotau, r = 0.57; p = 0.0284,) and amyloid (Abeta 42/40 ratio, r = 0.46; p = 0.03,). Additionally, SN median MRI contrast significantly correlated with novelty responses in the hippocampus in the CSF subsample and also in amyloid positive but not negative (Abeta 42/40 ratio&lt;0.08, n = 26) individuals. Finally, recognition memory (p&lt;0.001) was significantly decreased in Abeta positive compared to negative individuals.ConclusionWe show that significant degeneration to the SN in AD dementia and pathological Abeta 42/40 levels are associated with poorer recognition memory for novel stimuli. Moreover, associations between SN median MRI contrast and novelty responses differed between amyloid positive and negative individuals. These results indicate that degeneration to the SN may contribute to memory dysfunction in AD dementia which may be linked to pathological amyloid levels.

Midbrain-Hippocampus Structural Connectivity Selectively Predicts Motivated Memory Encoding.

Motivation is a powerful driver of learning and memory. Functional MRI studies show that interactions among the dopaminergic midbrain substantia nigra/ventral tegmental area (SN/VTA), hippocampus, and nucleus accumbens (NAc) are critical for motivated memory encoding. However, it is not known whether these effects are transient and purely functional, or whether individual differences in the structure of this circuit underlie motivated memory encoding. To quantify individual differences in structure, diffusion-weighted MRI and probabilistic tractography were used to quantify SN/VTA-striatum and SN/VTA-hippocampus pathways associated with motivated memory encoding in humans. Male and female participants completed a motivated source memory paradigm. During encoding, words were randomly assigned to one of three conditions, reward ($1.00), control ($0.00), or punishment (-$1.00). During retrieval, participants were asked to retrieve item and source information of the previously studied words and were rewarded or penalized according to their performance. Source memory for words assigned to both reward and punishment conditions was greater than those for control words, but there were no differences in item memory based on value. Anatomically, probabilistic tractography results revealed a heterogeneous, topological arrangement of the SN/VTA. Tract density measures of SN/VTA-hippocampus pathways were positively correlated with individual differences in reward-and-punishment-modulated memory performance, whereas density of SN/VTA-striatum pathways showed no association. This novel finding suggests that pathways emerging from the human SV/VTA are anatomically separable and functionally heterogeneous. Individual differences in structural connectivity of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding.SIGNIFICANCE STATEMENT Functional MRI studies show that interactions among the SN/VTA, hippocampus, and NAc are critical for motivated memory encoding. This has led to competing theories that posit either SN/VTA-NAc reward prediction errors or SN/VTA-hippocampus signals underlie motivated memory encoding. Additionally, it is not known whether these effects are transient and purely functional or whether individual differences in the structure of these circuits underlie motivated memory encoding. Using diffusion-weighted MRI and probabilistic tractography, we show that tract density measures of SN/VTA-hippocampus pathways are positively correlated with motivated memory performance, whereas density of SN/VTA-striatum pathways show no association. This finding suggests that anatomic individual differences of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding.

Category-specific memory encoding in the medial temporal lobe and beyond: the role of reward.

The medial temporal lobe (MTL), including the hippocampus (HC), perirhinal cortex (PRC), and parahippocampal cortex (PHC), is central to memory formation. Reward enhances memory through interplay between the HC and substantia nigra/ventral tegmental area (SNVTA). While the SNVTA also innervates the MTL cortex and amygdala (AMY), their role in reward-enhanced memory is unclear. Prior research suggests category specificity in the MTL cortex, with the PRC and PHC processing object and scene memory, respectively. It is unknown, however, whether reward modulates category-specific memory processes. Furthermore, no study has demonstrated clear category specificity in the MTL for encoding processes contributing to subsequent recognition memory. To address these questions, we had 39 healthy volunteers (27 for all memory-based analyses) undergo functional magnetic resonance imaging while performing an incidental encoding task pairing objects or scenes with high or low reward, followed by a next-day recognition test. Behaviorally, high reward preferably enhanced object memory. Neural activity in the PRC and PHC reflected successful encoding of objects and scenes, respectively. Importantly, AMY encoding effects were selective for high-reward objects, with a similar pattern in the PRC. The SNVTA and HC showed no clear evidence of successful encoding. This behavioral and neural asymmetry may be conveyed through an anterior-temporal memory system, including the AMY and PRC, potentially in interplay with the ventromedial prefrontal cortex.

The 5-HT1A receptor antagonist WAY-100635 decreases motor/exploratory behaviors and nigrostriatal and mesolimbocortical dopamine D2/3 receptor binding in adult rats

Serotonin(5-HT)ergic projections run from the raphe nuclei to dopamin(DA)ergic cells in substantia nigra/ventral tegmental area (SN/VTA) and to the terminal fields of DA neurons in nucleus accumbens, caudateputamen and neocortex. In the present studies, we assessed the effect of the 5-HT1A receptor (R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarbox-amide maleate (WAY-100635) on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. D2/3R binding was determined in the same animals after systemic application of WAY-100635 (0.4 mg/kg) and 0.9% saline (SAL), respectively, with [123I]IBZM as SPECT ligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after treatment with WAY-100635 or SAL, motor/exploratory behaviors were assessed for 30 min in two different batches of animals in an open field. WAY-100635 reduced D2/3R binding in caudateputamen, thalamus, frontal cortex, parietal cortex and ventral hippocampus relative to SAL. Network analysis of regional binding data after WAY-100635 yielded positive connections between (1) caudateputamen and substantia nigra/ventral tegmental area, (2) caudateputamen and ventral hippocampus, (3) substantia nigra/ventral tegmental area and parietal cortex, (4) thalamus and dorsal hippocampus and (5) frontal cortex and parietal cortex, which were not present after SAL. Moreover, WAY-100635 decreased parameters of motor activity (overall activity, ambulation duration and frequency) but increased the duration of grooming behavior relative to SAL. The effect on exploration was time-dependent with an early increase and a subsequent decrease of behavioral parameters (rearing duration and frequency, frequency of head-shoulder motility). For WAY-100635, findings imply a region-specificity as well as a time-dependency of DAergic action.

Involvement of GPR17 in Neuronal Fibre Outgrowth.

Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.

Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding.

Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.

Cross-Scanner Harmonization of Neuromelanin-Sensitive MRI for Multisite Studies.

Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a validated measure of neuromelanin concentration in the substantia nigra-ventral tegmental area (SN-VTA) complex and is a proxy measure of dopaminergic function with potential as a noninvasive biomarker. The development of generalizable biomarkers requires large-scale samples necessitating harmonization approaches to combine data collected across sites. To develop a method to harmonize NM-MRI across scanners and sites. Prospective. A total of 128 healthy subjects (18-73 years old; 45% female) from three sites and five MRI scanners. 3.0 T; NM-MRI two-dimensional gradient-recalled echo with magnetization-transfer pulse and three-dimensional T1-weighted images. NM-MRI contrast (contrast-to-noise ratio [CNR]) maps were calculated and CNR values within the SN-VTA (defined previously by manual tracing on a standardized NM-MRI template) were determined before harmonization (raw CNR) and after ComBat harmonization (harmonized CNR). Scanner differences were assessed by calculating the classification accuracy of a support vector machine (SVM). To assess the effect of harmonization on biological variability, support vector regression (SVR) was used to predict age and the difference in goodness-of-fit (Δr) was calculated as the correlation (between actual and predicted ages) for the harmonized CNR minus the correlation for the raw CNR. Permutation tests were used to determine if SVM classification accuracy was above chance level and if SVR Δr was significant. A P-value <0.05 was considered significant. In the raw CNR, SVM MRI scanner classification was above chance level (accuracy=86.5%). In the harmonized CNR, the accuracy of the SVM was at chance level (accuracy=29.5%; P=0.8542). There was no significant difference in age prediction using the raw or harmonized CNR (Δr=-0.06; P=0.7304). ComBat harmonization removes differences in SN-VTA CNR across scanners while preserving biologically meaningful variability associated with age. 2 TECHNICAL EFFICACY: 1.

Neural dysfunctions following experimental permanent occlusions of bilateral common carotid arteries cause an increase of rat voluntary alcohol drinking behavior.

We have previously reported that ischemic animal models treated with a respiratory inhibitor, rotenon, show an increased voluntary alcohol intake. Although it is clear that ischemic brain, as a result of reduced-blood flow, shows pathological events and/or neuro-degenerations apparently, little is known of causal relationship between the mechanism of neural dysfunction and voluntary alcohol consumption. Authors have investigated effects of permanent two-vessel occlusion (p2VO) on rat voluntary alcohol drinking behavior. In first experiment the p2VO-treated rats showed an increase of voluntary alcohol drinking behavior, as compared with sham controls. Using brain microdialysis technique, increases of only nucleus accumbens (ACC) dopamine (DA) releases were suppressed in the p2VO-treated rats significantly, following the high K+ (40mM) perfusion through the microdialysis probe membrane. Alcohol (200mM) perfusion-induced DA and serotonin (5-HT) releases in the ACC of the p2VO-treated rats were suppressed significantly in the second experiment, as compared with the sham-treated rats. In third experiment p2VO-treated rats showed significant decreases of the contents of DA, not 5-HT, in the ACC, caudate-putamen (C/P), ventral tegmental area-substantia nigra (VT/SN) and lateral hypothalamus (LH). Dopaminergic neurons in the ACC showed more functional vulnerability against the p2VO treatments, as compared with the serotonergic neurons. An increase of alcohol intake in the p2VO-treated rats means the compensation for the neural degeneration of the dopaminergic system in the ACC consisted brain rewarding system. It was likely suggested that neural disturbance of higher functions involved with incomplete global brain ischemia leads the risk of an abnormal alcohol drinking in human.

Dopamine D2/3 receptor availability in cocaine use disorder individuals with obesity as measured by [11C]PHNO PET

BackgroundPositron emission tomography (PET) work with the dopamine D3 receptor (D3R) preferring ligand [11C]PHNO in obese individuals has demonstrated higher binding and positive correlations with body mass index (BMI) in otherwise healthy individuals. These findings implicated brain reward areas including the substantia nigra/ventral tegmental area (SN/VTA) and pallidum. In cocaine use disorder (CUD), similar SN/VTA binding profiles have been found compared to healthy control subjects. This study investigates whether BMI-[11C]PHNO relationships are similar in individuals with CUD. MethodsNon-obese CUD subjects (N = 12) were compared to age-matched obese CUD subjects (N = 14). All subjects underwent [11C]PHNO acquisition using a High Resolution Research Tomograph PET scanner. Parametric images were computed using the simplified reference tissue model with cerebellum as the reference region. [11C]PHNO measures of receptor availability were calculated and expressed as non-displaceable binding potential (BPND). ResultsIn between-group analyses, D2/3R availability in non-obese and obese CUD groups was not significantly different overall. BMI was inversely correlated withBPND in the SN/VTA (r = -0.45, p = 0.02 uncorrected) in all subjects. ConclusionThese data suggest that obesity in CUD was not associated with significant differences in D2/3R availability. This in contrast to previous findings in non-CUD individuals that found increased availability of D3Rs in the SN/VTA associated with obesity. These findings could potentially reflect dysregulation of D3R in CUD, impacting how affected individuals respond to natural stimuli such as food.

Noradrenergic correlates of chronic cocaine craving: neuromelanin and functional brain imaging

Preclinical studies have implicated noradrenergic (NA) dysfunction in cocaine addiction. In particular, the NA system plays a central role in motivated behavior and may partake in the regulation of craving and drug use. Yet, human studies of the NA system are scarce, likely hampered by the difficulty in precisely localizing the locus coeruleus (LC). Here, we used neuromelanin imaging to localize the LC and quantified LC neuromelanin signal (NMS) intensity in 44 current cocaine users (CU; 37 men) and 59 nondrug users (NU; 44 men). We also employed fMRI to investigate cue-induced regional responses and LC functional connectivities, as quantified by generalized psychophysiological interaction (gPPI), in CU. Imaging data were processed by published routines and the findings were evaluated with a corrected threshold. We examined how these neural measures were associated with chronic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ). Compared to NU, CU demonstrated higher LC NMS for all probabilistic thresholds defined of 50–90% of the peak. In contrast, NMS of the ventral tegmental area/substantia nigra (VTA/SN) did not show significant group differences. Drug as compared to neutral cues elicited higher activations of many cortical and subcortical regions, none of which were significantly correlated with CCQ score. Drug vs. neutral cues also elicited “deactivation” of bilateral parahippocampal gyri (PHG) and PHG gPPI with a wide array of cortical and subcortical regions, including the ventral striatum and, with small volume correction, the LC. Less deactivation of the PHG (r = 0.40, p = 0.008) and higher PHG-LC gPPI (r = 0.44, p = 0.003) were positively correlated with the CCQ score. In contrast, PHG-VTA/SN connectivity did not correlate with the CCQ score. Together, chronic cocaine exposure may induce higher NMS intensity, suggesting neurotoxic effects on the LC. The correlation of cue-elicited PHG LC connectivity with CCQ score suggests a noradrenergic correlate of chronic cocaine craving. Potentially compensating for memory functions as in neurodegenerative conditions, cue-elicited PHG LC circuit connectivity plays an ill-adaptive role in supporting cocaine craving.

Chronic alcohol exposure differentially modulates structural and functional properties of amygdala: A cross‐sectional study

AbstractAnimal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala grey‐matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed‐based approach and amygdala GMV in abstinent ADP (n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the ADP group showed that amygdala‐SN/VTA RSFC increases were primarily associated with cumulative alcohol exposure rather than age, whereas amygdala GMV reductions were primarily associated with age rather than cumulative alcohol exposure. The same association between age and amygdala GMV was not observed amongst HC. Importantly, amygdala GMV and amygdala‐SN/VTA RSFC were uncorrelated in ADP, and neither measure was correlated with abstinence length. These results suggest that chronic alcohol exposure is associated with persistent elevations in amygdala‐SN/VTA RSFC and accelerated age‐related grey‐matter atrophy through potentially distinct mechanisms.

Identification of internet gaming disorder individuals based on ventral tegmental area resting-state functional connectivity.

Objective neuroimaging markers are imminently in need for more accurate clinical diagnosis of Internet gaming disorder (IGD). Recent neuroimaging evidence suggested that IGD is associated with abnormalities in the mesolimbic dopamine (DA) system. As the key nodes of the DA pathways, ventral tegmental area (VTA) and substantia nigra (SN) and their connected brain regions may serve as potential markers to identify IGD. Therefore, we aimed to develop optimal classifiers to identify IGD individuals by using VTA and bilateral SN resting-state functional connectivity (RSFC) patterns. A dataset including 146 adolescents (66 IGDs and 80 healthy controls (HCs)) was used to build classification models and another independent dataset including 28 subjects (14 IGDs and 14 HCs) was employed to validate the generalization ability of the models. Multi-voxel pattern analysis (MVPA) with linear support vector machine (SVM) was used to select the features. Our results demonstrated that the VTA RSFC circuits successfully identified IGD individuals (mean accuracy: 86.1%, mean sensitivity: 84.5%, mean specificity: 86.6%, the mean area under the receiver operating characteristic curve: 0.91). Furthermore, the independent generalization ability of the VTA RSFC classifier model was also satisfied (accuracy = 78.5%, sensitivity = 71.4%, specificity = 85.8%). The VTA connectivity circuits that were selected as distinguishing features were mainly included bilateral thalamus, right hippocampus, right pallidum, right temporal pole superior gyrus and bilateral temporal superior gyrus. These findings demonstrated that the potential of the resting-state neuroimaging features of VTA RSFC as objective biomarkers for the IGD clinical diagnosis in the future.

Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression.

Late-life depression (LLD) is a prevalent and disabling condition in older adults that is often accompanied by slowed processing and gait speed. These symptoms are related to impaired dopamine function and sometimes remedied by levodopa (L-DOPA). In this study, we recruited 33 older adults with LLD to determine the association between a proxy measure of dopamine function-neuromelanin-sensitive magnetic resonance imaging (NM-MRI)-and baseline slowing measured by the Digit Symbol test and a gait speed paradigm. In secondary analyses, we also assessed the ability of NM-MRI to predict L-DOPA treatment response in a subset of these patients (N = 15) who received 3 weeks of L-DOPA. We scanned a further subset of these patients (N = 6) with NM-MRI at baseline and after treatment to preliminarily evaluate the effects of L-DOPA treatment on the NM-MRI signal. We found that lower baseline NM-MRI correlated with slower baseline gait speed (346 of 1807 substantia nigra-ventral tegmental area (SN-VTA) voxels, Pcorrected = 0.038), particularly in the more medial, anterior, and dorsal SN-VTA. Secondary analyses failed to show an association between baseline NM-MRI and treatment-related changes in gait speed, processing speed, or depression severity (all Pcorrected > 0.361); we however found preliminary evidence of increases in the NM-MRI signal 3 weeks post-treatment with L-DOPA compared to baseline (200 of 1807 SN-VTA voxels; Pcorrected = 0.046), although the small sample size of these preliminary analyses warrants caution in their interpretation and future replications. Overall, our findings indicate that NM-MRI is sensitive to variability in gait speed in patients with LLD, suggesting this non-invasive MRI measure may provide a promising marker for dopamine-related psychomotor slowing in geriatric neuropsychiatry.

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat.

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1mg/kg), the GABAAR antagonist bicuculline (1mg/kg), the NMDAR agonist d-cycloserine (20mg/kg) or the NMDAR antagonist amantadine (40mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.

The expression of DARPP-32 in adult male zebra finches (Taenopygia guttata).

Although the catecholaminergic circuitry in the zebra finch brain has been well studied, there is little information regarding the postsynaptic targets of dopamine. To answer this question, we looked at overall patterns of immunoreactivity for DARPP-32 (a dopamine and cAMP-regulated phosphoprotein, present mostly in dopaminoceptive neurons) in adult male zebra finches. Our results demonstrated that as in mammals and other avian species, DARPP-32 expression was highest in both medial and lateral striatum. Interestingly, a specific pattern of immunoreactivity was observed in the song control system, with 'core' song control regions, that is, LMANcore (lateral magnocellular nucleus of the anterior nidopallium), RA (nucleus robustus arcopallialis) and HVC being less immunoreactive for DARPP-32 than 'shell' areas such as LMANshell, RAcup, AId (intermediate arcopallium) and HVCshelf. Our results suggest that whereas dopamine may modulate the shell pathways at various levels of the AFP, dopaminergic modulation of the core pathway occurs mainly through Area X, a basal ganglia nucleus. Further, secondary sensory cortices including the perientopallial belt, Fields L1 and L3 had higher DARPP-32-immunoreactivity than primary sensory cortical areas such as the pallial basolateral nucleus, entopallium proper and Field L2, corresponding to somatosensory, visual and auditory systems, respectively. We also found DARPP-32-rich axon terminals surrounding dopaminergic neurons in the ventral tegmental area-substantia nigra complex which in turn project to the striatum, suggesting that there may be a reciprocal modulation between these regions. Overall, DARPP-32 expression appears to be higher in areas involved in integrating sensory information, which further supports the role of this protein as a molecular integrator of different signal processing pathways.

Brain responses to different types of salience in antipsychotic na\xefve first episode psychosis: An fMRI study

Abnormal salience processing has been suggested to contribute to the formation of positive psychotic symptoms in schizophrenia and related conditions. Previous research utilising reward learning or anticipation paradigms has demonstrated cortical and subcortical abnormalities in people with psychosis, specifically in the prefrontal cortex, the dopaminergic midbrain and the striatum. In these paradigms, reward prediction errors attribute motivational salience to stimuli. However, little is known about possible abnormalities across different forms of salience processing in psychosis patients, and whether any such abnormalities involve the dopaminergic midbrain. The aim of our study was, therefore, to investigate possible alterations in psychosis in neural activity in response to various forms of salience: novelty, negative emotion, targetness (task-driven salience) and rareness/deviance. We studied 14 antipsychotic naïve participants with first episode psychosis, and 37 healthy volunteers. During fMRI scanning, participants performed a visual oddball task containing these four forms of salience. Psychosis patients showed abnormally reduced signalling in the substantia nigra/ventral tegmental area (SN/VTA) for novelty, negative emotional salience and targetness; reduced striatal and occipital (lingual gyrus) signalling to novelty and negative emotional salience, reduced signalling in the amygdala, anterior cingulate cortex and parahippocamal gyrus to negative emotional salience, and reduced cerebellar signalling to novelty and negative emotional salience. Our results indicate alterations of several forms of salience processing in patients with psychosis in the midbrain SN/VTA, with additional subcortical and cortical regions also showing alterations in salience signalling, the exact pattern of alterations depending on the form of salience in question.

Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers.

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC+/- mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/- mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

S154. THE ROLE OF DOPAMINE IN PROCESSING THE MEANINGFUL INFORMATION OF OBSERVATIONS, AND IMPLICATIONS FOR THE ABERRANT SALIENCE HYPOTHESIS OF SCHIZOPHRENIA

BackgroundThe aberrant salience hypothesis of schizophrenia proposes that symptoms such as paranoia arise when behavioural salience is attributed to neutral stimuli. Mesolimbic dopamine dysfunction is thought to be central to this mechanism; building on findings that activity in this pathway conveys a (signed) reward prediction error signal. Given that many psychotic symptoms are not explicitly related to reward learning, it is relevant that recent studies in rodents have demonstrated a role for midbrain dopamine neurons in value-neutral associative learning. Direct evidence for this role in humans, however, is lacking.In this study we asked whether the mesolimbic dopamine circuit is involved in encoding the value-neutral meaningful information of observations, using a model-based functional magnetic resonance imaging (fMRI) task and dopamine positron emission tomography (PET). We define ‘meaningful information’ as the degree to which an observation results in a belief-update to an agent’s internal model of the environment (Kullback-Leibler divergence from prior to posterior beliefs; ‘Bayesian surprise’).MethodsParticipants were tasked to infer the current (hidden) state of the environment, using partially-informative observations at each trial, and then report their belief at the end of each trial. Participant beliefs were modelled using a Hidden Markov Model of the task and iterative application of Bayes’ rule, allowing us to quantify the Bayesian surprise (meaningful information content) associated with a trial observation. Crucially, our task de-correlated Bayesian surprise from both the pure sensory unexpectedness of an observation (unexpected but meaningless information) and its signed reward prediction error. 39 healthy participants (22M, mean age 26y) performed 180 task trials within an fMRI scanner. 36 participants also had a [11C]-(+)-4-propyl-9-hydroxy-naphthoxazine (PHNO) PET scan to quantify dopamine-2/3 receptor (D2/3R) availability. 17 participants additionally had a second PET scan 3hrs post 0.5mg/kg oral dexamphetamine, to quantify striatal dopamine release capacity. Neuroimaging analyses were restricted to the bilateral substantia nigra/ventral tegmental area (SN/VTA) and ventral striatum (VS).ResultsOur computational model closely predicted participant behaviour (R2= .67), and there was a negative correlation between subclinical paranoia and the degree to which participant behaviour approximated normative Bayesian performance (rho = -.60, P<0.001). Neuronal activation encoding the meaningful information content of an observation (Bayesian surprise) was present in SN/VTA and VS (both P(peak)<0.05, SVC), whereas no such encoding was present for sensory unexpectedness or reward-prediction error. Crucially, activation encoding Bayesian surprise was inversely correlated with D2/3R availability in the SN/VTA (rho = -.43, P=0.009), consistent with a tonic inhibitory role for midbrain D2/3Rs. Moreover, activation encoding Bayesian surprise was inversely related to dopamine release capacity in the VS (rho = -.66, P=0.005), indicating that subjects with high dopamine release capacity showed blunted striatal activation in response to belief-changing information, as is also found in schizophrenia.DiscussionWe provide direct evidence in humans that a mesolimbic dopamine circuit is involved in encoding the meaningful information content of observations, distinct from its involvement in processing signed reward prediction error. These results implicate dopamine in a wider range of function than reward learning, including updating a predictive associative model of the world, and are therefore relevant for the aberrant salience hypothesis of schizophrenia.