Ventral Tegmental Area Connectivity Research Articles

Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses.

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to VTA dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.

The role of ventral tegmental area in chronic stroke rehabilitation: an exploratory study.

The acknowledged role of external rewards in chronic stroke rehabilitation, offering positive reinforcement and motivation, has significantly contributed to patient engagement and perseverance. However, the exploration of self-reward's importance in this context remains limited. This study aims to investigate the functional connectivity of the ventral tegmental area (VTA), a key node in the brain's reward circuitry, during motor task-based rehabilitation and its correlation with the recovery process. Twelve right-handed healthy volunteers (4 men, 8 women, aged 57.4 ± 11.3 years) and twelve chronic stroke patients (5 men, 7 women, aged 48.1 ± 11.1 years) with clinically significant right-sided motor impairment (mean FM-UE score of 27.6 ± 8.7) participated. The analysis employed the CONN toolbox to assess the association between motor tasks and VTA connectivity using psychophysiological interaction (PPI). PPI analysis revealed motor-dependent changes in VTA connectivity, particularly with regions within the motor circuitry, cerebellum, and prefrontal cortex. Notably, stronger connectivity between the ipsilesional VTA and cerebellum was observed in healthy controls compared to chronic stroke patients, highlighting the importance of VTA-cerebellum interactions in motor function. Stroke patients' motor performance was associated with VTA modulation in areas related to both motor tasks and reward processing, emphasizing the role of self-reward processes in rehabilitation. Changes in VTA influence on motor circuitry were linked to improvements in motor performance resulting from rehabilitation. Our findings underscore the potential of neuroimaging techniques in quantifying and predicting rehabilitation outcomes by examining self-reward processes. The observed associations between VTA connectivity and motor performance in both healthy and stroke-affected individuals emphasize the role of psychological factors, particularly self-reward, in the rehabilitation process. This study contributes valuable insights into the intricate interplay between reward circuits and motor function, highlighting the importance of addressing psychological dimensions in neurorehabilitation strategies.

Exploring the link between functional connectivity of ventral tegmental area and physical fitness in schizophrenia and healthy controls

Decreased physical fitness and being overweight are highly prevalent in schizophrenia, represent a major risk factor for comorbid cardio-vascular diseases and decrease the life expectancy of the patients. Thus, it is important to understand the underlying mechanisms that link psychopathology and weight gain. We hypothesize that the dopaminergic reward system plays an important role in this. We analyzed the seed-based functional connectivity (FC) of the ventral tegmental area (VTA) in a group of schizophrenic patients (n=32) and age-, as well as gender-, matched healthy controls (n=27). We then correlated the resting-state results with physical fitness parameters, obtained in a fitness test, and psychopathology. The FC analysis revealed decreased functional connections between the VTA and the anterior cingulate cortex (ACC), as well as the dorsolateral prefrontal cortex, which negatively correlated with psychopathology, and increased FC between the VTA and the middle temporal gyrus in patients compared to healthy controls, which positively correlated with psychopathology. The decreased FC between the VTA and the ACC of the patient group further positively correlated with total body fat (p = .018, FDR-corr.) and negatively correlated with the overall physical fitness (p = .022). This study indicates a link between decreased physical fitness and higher body fat with functional dysconnectivity between the VTA and the ACC. These findings demonstrate that a dysregulated reward system might also be involved in comorbidities and could pave the way for future lifestyle therapy interventions.

Altered neural reward processing is associated with reward-related decision-making in adolescents with severe obesity

Obesity is associated with altered food-related reward processing, but its impact on non-food reward remains unclear. This question is both timely due to rising rates of severe obesity and important because adolescence is a period of heightened reward seeking behavior. We used computational modeling and functional magnetic resonance imaging (fMRI) to examine monetary reward processing using classic experimental tasks in 35 adolescents (14-18 years-old, 13 male) with severe obesity (OB; n=18) and without obesity (nonOB; n=17). Participants completed the Balloon Analog Risk Taking Task (BART) to assess reward-related decision-making and the Monetary Incentive Delay (MID) task to assess neural correlates of reward anticipation. BART model-based parameters revealed no differences in reward sensitivity but less adaptive decision-making (response consistency) in OB compared to nonOB. Other metrics (e.g., number of balloons popped, number of pumps, and total points) did not differ between groups. During MID reward anticipation, OB had lower activation than nonOB in ventral tegmental area (VTA) and prefrontal cortex, canonical regions for reward and cognitive control, respectively. Weight status moderated associations between VTA activation and BART metrics such that higher VTA activation was associated with more risky decision-making (more popped balloons) in OB but not nonOB. Functional connectivity of VTA with right inferior frontal gyrus (IFG) and left superior temporal gyrus (STG) was greater higher in OB than nonOB. Associations between value-related VTA-STG connectivity and BART metrics were moderated by weight status such that higher connectivity was associated with greater number of pumps and points for nonOB and less risky decision-making for OB. Therefore, differences in activation and connectivity between groups may suggest differences in decision-making strategies. Together, findings reveal that VTA, prefrontal, and temporal engagement during monetary reward anticipation differs in OB and nonOB adolescents and may contribute to individual differences in reward-related decision-making. Such domain-general alteration of reward processing may have far reaching consequences, not only for food intake but also functions central to motivational behavior such as learning and socialization during adolescence, a sensitive period in development. These findings highlight the importance of considering reward more broadly when designing and tailoring behavioral interventions in adolescent obesity

Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer's Disease: Implications for Treatment.

Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer's disease (AD). In this study, we longitudinally investigated by resting-state fMRI (rs-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. A cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and rs-fMRI to assess VTA connectivity at baseline and at follow-up. At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-Converters compared to non-converters remained substantially unchanged at 24-month follow-up. This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression.

Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity

Early life stress increases risk for later psychopathology, due in part to changes in dopaminergic brain systems that support reward processing and motivation. Work in animals has shown that early life stress has a profound impact on the ventral tegmental area (VTA), which provides dopamine to regions including nucleus accumbens (NAcc), anterior hippocampus, and medial prefrontal cortex (mPFC), with cascading effects over the course of development. However, little is known about how early stress exposure shifts the developmental trajectory of mesocorticolimbic circuitry in humans. In the current study, 88 four- to nine-year-old children participated in resting-state fMRI. Parents completed questionnaires on their children's chronic stress exposure, including socioeconomic status (SES) and adverse childhood experiences (ACEs). We found an age x SES interaction on VTA connectivity, such that children from higher SES backgrounds showed a positive relationship between age and VTA-mPFC connectivity. Similarly, we found an age x ACEs exposure interaction on VTA connectivity, such that children with no ACEs exposure showed a positive relationship between age and VTA-mPFC connectivity. Our findings suggest that early stress exposure relates to the blunted maturation of VTA connectivity in young children, which may lead to disrupted reward processing later in childhood and beyond.

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.

Ventral tegmental area dysfunction affects decision-making in patients with myotonic dystrophy type-1

The clinical manifestations of Myotonic Dystrophy type-1 (DM1) are associated with a complex mixture of multisystem features including cognitive dysfunctions that strongly impact on patients' social and occupational functioning. Decision making, a function controlled by dopaminergic circuitry, is critical for succeeding in one's social and professional life. We tested here the hypothesis that altered connectivity of the ventral tegmental area (VTA), one of the major sources of diffuse dopaminergic projections in the brain, might account for some higher-level dysfunctions observed in patients with DM1. In this case–control study, we recruited 31 patients with DM1 and 26 healthy controls who underwent the IOWA Gambling task and resting-state functional MRI (RS-fMRI) at 3T. Functional connectivity of the VTA was assessed using RS-fMRI. VTA connectivity was compared between 25 DM1 patients and all the controls, and the presence of associations between VTA connectivity and IOWA Gambling task performance was also investigated. DM1 patients performed significantly worse than controls at the IOWA Gambling task. A significant increase of functional connectivity was observed between VTA and the left supramarginal and superior temporal gyri in DM1 patients. Patients' IOWA Gambling task net-scores were strictly associated with VTA-driven functional connectivity in the bilateral supplementary motor area and right precentral gyrus. This study demonstrates a prominent deficit of decision-making in patients with DM1. It might be related to increased connectivity between VTA and brain areas critically involved in the reward/punishment system and social cognition. These findings indicate that dopaminergic function is a potential target for pharmacological and non-pharmacological interventions in DM1.

Mitogen-activated protein kinase phosphatase-2 deletion modifies ventral tegmental area function and connectivity and alters reward processing.

Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning, and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.

The influence of oxytocin and vasopressin on men’s judgments of social dominance and trustworthiness: An fMRI study of neutral faces

Cues signaling trust and dominance are crucial for social life. Previous studies on the effects of oxytocin (OT) nasal sprays on trustworthiness evaluations have been inconsistent and its influence on dominance is unknown. Vasopressin (AVP) may also influence social cue perception, but even fewer investigations have evaluated this possibility. We evaluated the effects of intranasal OT and AVP compared to placebo control during three double-blinded functional magnetic resonance imaging sessions. Twenty males received a pseudo-randomized order of nasal spray conditions and rated the trustworthiness and dominance of neutral faces. OT increased facial dominance ratings compared to placebo. Neuroimaging results revealed an inverse relationship between brain activation and face ratings for OT compared to placebo in regions involved in processing emotional expressions. Specifically, the right superior temporal gyrus was attenuated as ratings increased and the left precuneus selectively diminished with increasing dominance ratings. Additionally, OT increased functional connectivity between frontoparietal regions and the right amygdala for faces rated as highly dominant, but OT increased connectivity between the fusiform gyrus, hippocampus, and bilateral ventral tegmental area (VTA) for faces perceived as highly trustworthy. Overall, OT increased the perception of dominance but did not influence trustworthiness judgments. However, we observed regional neural effects for OT that differed between judgments of trustworthiness and dominance. AVP attenuated left temporoparietal junction activity as face ratings increased, a result consistent with AVP influencing mentalization. AVP also led to increased left amygdala and right VTA connectivity with the putamen, which is consistent with cue-driven, habitual responses.

Resting State Functional Connectivity of Dorsal Raphe Nucleus and Ventral Tegmental Area in Medication-Free Young Adults With Major Depression.

Background: This study has, for the first time, investigated the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) resting state whole-brain functional connectivity in medication-free young adults with major depression (MDD), at baseline and in relationship to treatment response.Method: A total of 119 subjects: 78 MDD (24 ± 4 years.) and 41 Healthy Controls (HC) (24 ± 3 years) were included in the analysis. DRN and VTA ROIs anatomical templates were used to extract resting state fluctuations and used to derive whole-brain functional connectivity. Differences between MDD and HCs were examined, as well as the correlation of baseline Hamilton Depression and Anxiety scale scores to the baseline DRN and VTA connectivity. The relationship to treatment response was examined by investigating the correlation of the percentage decrease in depression and anxiety scale scores with baseline connectivity measures.Results: There was a significant decrease (p = 0.05; cluster-wise corrected) in DRN connectivity with the prefrontal and mid-cingulate cortex in the MDD group, compared with the HC group. DRN connectivity with temporal areas, including the hippocampus and amygdala, positively correlated with baseline depression scores (p = 0.05; cluster-wise corrected). VTA connectivity with the cuneus-occipital areas correlated with a change in depression scores (p = 0.05; cluster-wise corrected).Conclusion: Our results indicate the presence of DRN-prefrontal and DRN-cingulate cortex connectivity abnormalities in young medication-free depressed subjects when compared to HCs and that the severity of depressive symptoms correlates with DRN-amygdala/hippocampus connectivity. VTA connectivity with the parietal and occipital areas is related to antidepressant treatment associated with a decrease in depressive symptoms. Future studies need to be carried out in larger and different age group populations to confirm the findings of the study.

Invivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer's disease.

We assessed here functional connectivity changes in the locus coeruleus (LC) and ventral tegmental area (VTA) of patients with Alzheimer's disease (AD). We recruited 169 patients with either AD or amnestic mild cognitive impairment due to AD and 37 elderly controls who underwent cognitive and neuropsychiatric assessments and resting-state functional magnetic resonance imaging at 3T. Connectivity was assessed between LC and VTA and the rest of the brain. In amnestic mild cognitive impairment patients, VTA disconnection was predominant with parietal regions, while in AD patients, it involved the posterior nodes of the default-mode network. We also looked at the association between neuropsychiatric symptoms (assessed by the neuropsychiatric inventory) and VTA connectivity. Symptoms such as agitation, irritability, and disinhibition were associated with VTA connectivity with the parahippocampal gyrus and cerebellar vermis, while sleep and eating disorders were associated with VTA connectivity to the striatum and the insular cortex. This suggests a contribution of VTA degeneration to AD pathophysiology and to the occurrence of neuropsychiatric symptoms. We did not find evidence of LC disconnection, but this could be explained by the size of this nucleus, which makes it difficult to isolate. These results are consistent with animal findings and have potential implications for AD prognosis and therapies.

The anatomy of the human medial forebrain bundle: Ventral tegmental area connections to reward-associated subcortical and frontal lobe regions.

IntroductionDespite their importance in reward, motivation, and learning there is only sparse anatomical knowledge about the human medial forebrain bundle (MFB) and the connectivity of the ventral tegmental area (VTA). A thorough anatomical and microstructural description of the reward related PFC/OFC regions and their connection to the VTA - the superolateral branch of the MFB (slMFB) - is however mandatory to enable an interpretation of distinct therapeutic effects from different interventional treatment modalities in neuropsychiatric disorders (DBS, TMS etc.). This work aims at a normative description of the human MFB (and more detailed the slMFB) anatomy with respect to distant prefrontal connections and microstructural features.Methods and materialHealthy subjects (n = 55; mean age ± SD, 40 ± 10 years; 32 females) underwent high resolution anatomical magnetic resonance imaging including diffusion tensor imaging. Connectivity of the VTA and the resulting slMFB were investigated on the group level using a global tractography approach. The Desikan/Killiany parceling (8 segments) of the prefrontal cortex was used to describe sub-segments of the MFB. A qualitative overlap with Brodmann areas was additionally described. Additionally, a pure visual analysis was performed comparing local and global tracking approaches for their ability to fully visualize the slMFB.ResultsThe MFB could be robustly described both in the present sample as well as in additional control analyses in data from the human connectome project. Most VTA- connections reached the superior frontal gyrus, the middel frontal gyrus and the lateral orbitofrontal region corresponding to Brodmann areas 10, 9, 8, 11, and 11m. The projections to these regions comprised 97% (right) and 98% (left) of the total relative fiber counts of the slMFB.DiscussionThe anatomical description of the human MFB shows far reaching connectivity of VTA to reward-related subcortical and cortical prefrontal regions - but not to emotion-related regions on the medial cortical surface - realized via the superolateral branch of the MFB. Local tractography approaches appear to be inferior in showing these far-reaching projections. Since these local approaches are typically used for surgical targeting of DBS procedures, the here established detailed map might - as a normative template - guide future efforts to target deep brain stimulation of the slMFB in depression and other disorders related to dysfunction of reward and reward-associated learning.

Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion.

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA GABA neurons that coexpress the neuropeptide galanin (LHA Gal ). These LHA Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA Gal neurons may represent a subpopulation of LHA GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA Gal or LHA GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA Gal or LHA GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA GABA neurons increased overall chow consumption. Additionally, LHA Gal or LHA GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA GABA neurons induced compulsive-like locomotor behavior; while LHA Gal neurons induced locomotor activity without compulsivity. Thus, LHA Gal neurons define a subpopulation of LHA GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified.SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHA GABA neurons is heterogeneous and largely undefined. Here we introduce LHA Gal neurons as a subset of LHA GABA neurons that lack direct innervation of the ventral tegmental area (VTA). LHA Gal neurons are sufficient to drive motivated feeding and locomotor activity similar to LHA GABA neurons, but without inducing compulsive-like behaviors, which we propose to require direct VTA innervation. Our study integrates galanin-expressing LHA neurons into our current understanding of the neuronal circuits and molecular mechanisms of the LHA that contribute to motivated feeding behaviors.

The Effects of Age, from Young to Middle Adulthood, and Gender on Resting State Functional Connectivity of the Dopaminergic Midbrain.

Dysfunction of the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is implicated in psychiatric disorders including attention-deficit/ hyperactivity disorder (ADHD), addiction, schizophrenia and movement disorders such as Parkinson’s disease (PD). Although the prevalence of these disorders varies by age and sex, the underlying neural mechanism is not well understood. The objective of this study was to delineate the distinct resting state functional connectivity (rsFC) of the VTA and SNc and examine the effects of age, from young to middle-adulthood, and sex on the rsFC of these two dopaminergic structures in a data set of 250 healthy adults (18–49 years of age, 104 men). Using blood oxygenation level dependent (BOLD) signals, we correlated the time course of the VTA and SNc to the time courses of all other brain voxels. At a corrected threshold, paired t-test showed stronger VTA connectivity to bilateral angular gyrus and superior/middle and orbital frontal regions and stronger SNc connectivity to the insula, thalamus, parahippocampal gyrus (PHG) and amygdala. Compared to women, men showed a stronger VTA/SNc connectivity to the left posterior orbital gyrus. In linear regressions, men but not women showed age-related changes in VTA/SNc connectivity to a number of cortical and cerebellar regions. Supporting shared but also distinct cerebral rsFC of the VTA and SNc and gender differences in age-related changes from young and middle adulthood in VTA/SNc connectivity, these new findings help advance our understanding of the neural bases of many neuropsychiatric illnesses that implicate the dopaminergic systems.

Reduced Ventral Tegmental Area–Hippocampal Connectivity in Children and Adolescents Exposed to Early Threat

BackgroundPreclinical data suggest that early life stress has detrimental effects on the brain’s dopaminergic system, particularly the mesocorticolimbic pathway. Altered dopamine function is thought to contribute to the development of stress-related pathologies; yet, little is known about the impact of early stress on dopamine systems during childhood and adolescence, when stress-related disorders frequently emerge. Here, we evaluate the impact of early threat exposure (violence, abuse) on functional connectivity of putative dopaminergic midbrain regions, the ventral tegmental area (VTA) and substantia nigra (SN), giving rise to mesocorticolimbic and nigrostriatal pathways, respectively. MethodsResting-state functional magnetic resonance imaging scans were completed in 43 trauma-exposed and 43 matched comparison youth (ages 7–17). Functional connectivity of the VTA and SN were compared between groups. ResultsThe trauma group demonstrated lower functional connectivity between the VTA and hippocampus. No group differences in SN connectivity were observed. Across all participants, there were age-related decreases in connectivity of both VTA and SN with the hippocampus, suggesting that age-related attenuations in VTA-hippocampal circuitry may be exacerbated in trauma-exposed youth. Higher levels of anxiety symptomology were associated with reduced SN–nucleus accumbens connectivity. ConclusionsPrevious research suggests that VTA-hippocampal circuitry is critical for the gating of new information into long-term memory. Lower connectivity in this circuitry suggests a novel mechanism that may serve to adaptively prevent the overwriting of a previously stored trauma memory while contributing to the broad range of cognitive and emotional difficulties linked to early stress exposure.

Brain activity classifies adolescents with and without a familial history of substance use disorders.

We aimed to uncover differences in brain circuits of adolescents with parental positive or negative histories of substance use disorders (SUD), when performing a task that elicits emotional conflict, testing whether the brain circuits could serve as endophenotype markers to distinguish these adolescents. We acquired functional magnetic resonance imaging data from 11 adolescents with a positive familial history of SUD (FH+ group) and seven adolescents with a negative familial history of SUD (FH− group) when performing an emotional stroop task. We extracted brain features from the conflict-related contrast images in group level analyses and granger causality indices (GCIs) that measure the causal interactions among regions. Support vector machine (SVM) was applied to classify the FH+ and FH− adolescents. Adolescents with FH+ showed greater activity and weaker connectivity related to emotional conflict, decision making and reward system including anterior cingulate cortex (ACC), prefrontal cortex (PFC), and ventral tegmental area (VTA). High classification accuracies were achieved with leave-one-out cross validation (89.75% for the maximum conflict, 96.71% when combining maximum conflict and general conflict contrast, 97.28% when combining activity of the two contrasts and GCIs). Individual contributions of the brain features to the classification were further investigated, indicating that activation in PFC, ACC, VTA and effective connectivity from PFC to ACC play the most important roles. We concluded that fundamental differences of neural substrates underlying cognitive behaviors of adolescents with parental positive or negative histories of SUD provide new insight into potential neurobiological mechanisms contributing to the elevated risk of FH+ individuals for developing SUD.

Functional Connectivity of Substantia Nigra and Ventral Tegmental Area: Maturation During Adolescence and Effects of ADHD

Dopaminergic (DArgic) pathways play crucial roles in brain function and their disruption is implicated in various neuropsychiatric diseases. Here, we demonstrate in 402 healthy children/adolescents (12 ± 3 years) and 704 healthy young adults (23 ± 5 years) that the functional connectivity of DA pathways matures significantly from childhood to adulthood and is different for healthy children and children with attention-deficit/hyperactivity disorder (ADHD; N = 203; 12 ± 3 years). This transition is characterized by age-related increases in the functional connectivity of the ventral tegmental area (VTA) with limbic regions and with the default mode network and by decreases in the connectivity of the substantia nigra (SN) with motor and medial temporal cortices. The changes from a predominant influence of SN in childhood/adolescence to a combined influence of SN and VTA in young adulthood might explain the increased vulnerability to psychiatric disorders, such as ADHD, early in life. We also show that VTA and SN connectivity networks were highly reproducible, which highlights their potential value as biomarkers for evaluating DArgic dysfunction in neuropsychiatric disorders.

Constructing dopaminergic signals in response to transient inputs in the ventral tegmental area

Event Abstract Back to Event Constructing dopaminergic signals in response to transient inputs in the ventral tegmental area Midbrain dopaminergic (DA) neurons signal motivational properties of natural reinforcers and addictive drugs important for the acquisition of conditioned behavior. The phasic DA response has been suggested to signal the discrepancy between the predicted and received reward, signaling a crucial learning term for reinforcement learning. The relevant dopaminergic neurons are found in two nuclei, the substantia nigra pars compacta and the ventral tegmental area (VTA). Electrophysiological recordings have demonstrated that transient inputs to the VTA, e.g. glutamatergic and cholinergic, convey salient information about the environment such as novel stimuli, received rewards, and reward predictive sensory cues. However, how transient inputs to the VTA are converted into DA output is poorly understood. In particular, the mechanism and location of the difference computation between expected and received rewards remain elusive. Furthermore, how addictive drugs such as nicotine modulate the VTA response to afferent inputs is not know. We address those questions using a biologically realistic model of the local VTA circuitry that includes both the neuronal dynamics and the kinetics of the relevant cholinergic receptors. We implement the neuronal microcircuit of the VTA in a network model accounting for the local VTA connectivity, the afferent projections to the VTA, the location of the nicotinic acetylcholine receptors (nAChRs) and their subtype-specific activation and desensitization properties. The VTA contains DAergic and GABAergic neurons receiving cholinergic (ACh) and glutamatergic (Glu) afferent input from subcortical and cortical structures. The DA response to endogenous acetylcholine is mediated by various nAChR subtypes expressed on: (i) DA neurons, (ii) GABAergic neurons, and (iii) presynaptic Glu terminals. The very same nAChRs are responsible for the impact of exogenous nicotine on DA signaling. The glutamatergic input activates synapses located on DA and GABAergic neurons. We first constrain our model by requiring it to account for both in vivo and in vitro experimental data obtained from recordings during nicotine exposures. In particular, we use the data to pin down the specific distribution of nAChRs. We then investigate how the VTA DA neurons respond to transient afferent inputs. We show that glutamatergic inputs phasically increase DA output. The impact of transient ACh inputs depends crucially on the the distribution of alpha4 beta2 subunit containing nAChRs in the VTA. Transient cholinergic inputs decrease DA output if alpha4 beta2 nAChRs are predominantly expressed by GABAergic cells. In this case, the VTA DA signal reflects the difference between the Glu and ACh inputs. This leads us to speculate that the "no reward" prediction signal from the habenula may be mediated via the cholinergic projections to the VTA. Finally, we show how nicotine subverts those signaling pathways by removing the impact of ACh signals on DA activity. Our investigations suggest biological mechanisms explaining how salient stimuli encoded in transient inputs to the VTA are translated into dopamine output. Conference: Computational and systems neuroscience 2009, Salt Lake City, UT, United States, 26 Feb - 3 Mar, 2009. Presentation Type: Poster Presentation Topic: Poster Presentations Citation: (2009). Constructing dopaminergic signals in response to transient inputs in the ventral tegmental area. Front. Syst. Neurosci. Conference Abstract: Computational and systems neuroscience 2009. doi: 10.3389/conf.neuro.06.2009.03.138 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 02 Feb 2009; Published Online: 02 Feb 2009. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Google Google Scholar PubMed Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

2205 Visual responses of monkey caudate neurons depend on reward expectancy

Despite their importance in reward, motivation, and learning there is only sparse anatomical knowledge about the human medial forebrain bundle (MFB) and the connectivity of the ventral tegmental area (VTA). A thorough anatomical and microstructural description of the reward related PFC/OFC regions and their connection to the VTA - the superolateral branch of the MFB (slMFB) - is however mandatory to enable an interpretation of distinct therapeutic effects from different interventional treatment modalities in neuropsychiatric disorders (DBS, TMS etc.). This work aims at a normative description of the human MFB (and more detailed the slMFB) anatomy with respect to distant prefrontal connections and microstructural features.Healthy subjects (n = 55; mean age ± SD, 40 ± 10 years; 32 females) underwent high resolution anatomical magnetic resonance imaging including diffusion tensor imaging. Connectivity of the VTA and the resulting slMFB were investigated on the group level using a global tractography approach. The Desikan/Killiany parceling (8 segments) of the prefrontal cortex was used to describe sub-segments of the MFB. A qualitative overlap with Brodmann areas was additionally described. Additionally, a pure visual analysis was performed comparing local and global tracking approaches for their ability to fully visualize the slMFB.The MFB could be robustly described both in the present sample as well as in additional control analyses in data from the human connectome project. Most VTA- connections reached the superior frontal gyrus, the middel frontal gyrus and the lateral orbitofrontal region corresponding to Brodmann areas 10, 9, 8, 11, and 11m. The projections to these regions comprised 97% (right) and 98% (left) of the total relative fiber counts of the slMFB.The anatomical description of the human MFB shows far reaching connectivity of VTA to reward-related subcortical and cortical prefrontal regions - but not to emotion-related regions on the medial cortical surface - realized via the superolateral branch of the MFB. Local tractography approaches appear to be inferior in showing these far-reaching projections. Since these local approaches are typically used for surgical targeting of DBS procedures, the here established detailed map might - as a normative template - guide future efforts to target deep brain stimulation of the slMFB in depression and other disorders related to dysfunction of reward and reward-associated learning.