Midbrain Dopamine Research Articles

Contributions of the Basal Ganglia to Visual Perceptual Decisions.

The basal ganglia (BG) make up a prominent nexus between visual and motor-related brain regions. In contrast to the BG's well-established roles in movement control and value-based decision making, their contributions to the transformation of visual input into an action remain unclear, especially in the context of perceptual decisions based on uncertain visual evidence. This article reviews recent progress in our understanding of the BG's contributions to the formation, evaluation, and adjustment of such decisions. From theoretical and experimental perspectives, the review focuses on four key stations in the BG network, namely, the striatum, pallidum, subthalamic nucleus, and midbrain dopamine neurons, which can have different roles and together support the decision process.

Selective encoding of reward predictions and prediction errors by globus pallidus subpopulations

Basal ganglia (BG) circuits help guide and invigorate actions using predictions of future rewards (values). Within the BG, the globus pallidus pars externa (GPe) may play an essential role in aggregating and distributing value information. We recorded from the GPe in unrestrained rats performing both Pavlovian and instrumental tasks to obtain rewards and distinguished neuronal subtypes by their firing properties across the wake/sleep cycle and optogenetic tagging. In both tasks, the parvalbumin-positive (PV+), faster-firing "prototypical" neurons showed strong, sustained modulation by value, unlike other subtypes, including the "arkypallidal" cells that project back to striatum. Furthermore, we discovered that a distinct minority (7%) of GP cells display slower, pacemaker-like firing and encode reward prediction errors (RPEs) almost identically to midbrain dopamine neurons. These cell-specific forms of GPe value representation help define the circuit mechanisms by which the BG contribute to motivation and reinforcement learning.

Axo-glial interactions between midbrain dopamine neurons and oligodendrocyte lineage cells in the anterior corpus callosum

Oligodendrocyte progenitor cells (OPCs) receive synaptic innervation from glutamatergic and GABAergic axons and can be dynamically regulated by neural activity, resulting in activity-dependent changes in patterns of axon myelination. However, it remains unclear to what extent other types of neurons may innervate OPCs. Here, we provide evidence implicating midbrain dopamine neurons in the innervation of oligodendrocyte lineage cells in the anterior corpus callosum and nearby white matter tracts of male and female adult mice. Dopaminergic axon terminals were identified in the corpus callosum of DAT-Cre mice after injection of an eYFP reporter virus into the midbrain. Furthermore, fast-scan cyclic voltammetry revealed monoaminergic transients in the anterior corpus callosum, consistent with the anatomical findings. Using RNAscope, we further demonstrate that ~ 40% of Olig2 + /Pdfgra + cells and ~ 20% of Olig2 + /Pdgfra- cells in the anterior corpus callosum express Drd1 and Drd2 transcripts. These results suggest that oligodendrocyte lineage cells may respond to dopamine released from midbrain dopamine axons, which could affect myelination. Together, this work broadens our understanding of neuron-glia interactions with important implications for myelin plasticity by identifying midbrain dopamine axons as a potential regulator of corpus callosal oligodendrocyte lineage cells.

Distinct roles of the orbitofrontal cortex, ventral striatum, and dopamine neurons in counterfactual thinking of decision outcomes.

Individuals often assess past decisions by comparing what was gained with what would have been gained had they acted differently. Thoughts of past alternatives that counter what actually happened are called "counterfactuals." Recent theories emphasize the role of the prefrontal cortex in processing counterfactual outcomes in decision-making, although how subcortical regions contribute to this process remains to be elucidated. Here we report a clear distinction among the roles of the orbitofrontal cortex, ventral striatum and midbrain dopamine neurons in processing counterfactual outcomes in monkeys. Our findings suggest that actually gained and counterfactual outcome signals are both processed in the cortico-subcortical network constituted by these regions but in distinct manners and integrated only in the orbitofrontal cortex in a way to compare these outcomes. This study extends the prefrontal theory of counterfactual thinking and provides key insights regarding how the prefrontal cortex cooperates with subcortical regions to make decisions using counterfactual information.

Intrinsic dopamine and acetylcholine dynamics in the striatum of mice.

External rewards such as food and money are potent modifiers of behaviour1,2. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic discharge of neurons that produce the neuromodulators dopamine (DA) and acetylcholine (ACh): midbrain DA neurons (DANs) fire a burst of action potentials that broadly elevates DA in the striatum3,4 at the same time that striatal cholinergic interneurons (CINs) produce a characteristic pause in firing5,6. These phasic responses are thought to create unique, temporally limited conditions that motivate action and promote learning7-11. However, the dynamics of DA and ACh outside explicitly rewarded situations remain poorly understood. Here we show that extracellular DA and ACh levels fluctuate spontaneously and periodically at a frequency of approximately 2 Hz in the dorsalstriatum of mice and maintain the same temporal relationship relative to one another as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within the striatum. Instead, we provide evidence that periodic fluctuations in striatal DA are inherited from midbrain DANs, while striatal ACh transients are driven by glutamatergic inputs, which act to locally synchronize the spiking of CINs. Together, our findings show that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents. The dominance of intrinsic rhythms in DA and ACh offers new insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.

Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

The Neurobiological Underpinnings of Obsessive-Compulsive Symptoms in Psychosis, Translational Issues for Treatment-Resistant Schizophrenia.

Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS) considered a transdiagnostic clinical continuum. The presence of symptoms pertaining to both schizophrenia and obsessive-compulsive disorder (OCD) may complicate pharmacological treatment and could contribute to lack or poor response to the therapy. Despite the clinical relevance, no reviews have been recently published on the possible neurobiological underpinnings of this comorbidity, which is still unclear. An integrative view exploring this topic should take into account the following aspects: (i) the implication for glutamate, dopamine, and serotonin neurotransmission as demonstrated by genetic findings; (ii) the growing neuroimaging evidence of the common brain regions and dysfunctional circuits involved in both diseases; (iii) the pharmacological modulation of dopaminergic, serotoninergic, and glutamatergic systems as current therapeutic strategies in schizophrenia OCS; (iv) the recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors; (v) the contribution of N-methyl-D-aspartate receptor subunits to both psychosis and OCD neurobiology. Finally, we discuss the potential role of the postsynaptic density as a structural and functional hub for multiple molecular signaling both in schizophrenia and OCD pathophysiology.

Altered Thalamocortical Signaling in a Mouse Model of Parkinson's Disease.

Activation of the primary motor cortex (M1) is important for the execution of skilled movements and motor learning, and its dysfunction contributes to the pathophysiology of Parkinson's disease (PD). A well-accepted idea in PD research, albeit not tested experimentally, is that the loss of midbrain dopamine leads to decreased activation of M1 by the motor thalamus. Here, we report that midbrain dopamine loss altered motor thalamus input in a laminar- and cell type-specific fashion and induced laminar-specific changes in intracortical synaptic transmission. Frequency-dependent changes in synaptic dynamics were also observed. Our results demonstrate that loss of midbrain dopaminergic neurons alters thalamocortical activation of M1 in both male and female mice, and provide novel insights into circuit mechanisms for motor cortex dysfunction in a mouse model of PD.SIGNIFICANCE STATEMENT Loss of midbrain dopamine neurons increases inhibition from the basal ganglia to the motor thalamus, suggesting that it may ultimately lead to reduced activation of primary motor cortex (M1). In contrast with this line of thinking, analysis of M1 activity in patients and animal models of Parkinson's disease report hyperactivation of this region. Our results are the first report that midbrain dopamine loss alters the input-output function of M1 through laminar and cell type specific effects. These findings support and expand on the idea that loss of midbrain dopamine reduces motor cortex activation and provide experimental evidence that reconciles reduced thalamocortical input with reports of altered activation of motor cortex in patients with Parkinson's disease.

Nuclei and tracts in the epithalamus of crocodiles.

The epithalamus, an area of the dorsal diencephalon found in all vertebrates, consists of the habenula, the subhabenular nuclei, and associated tracts. The habenula is itself divisible into two parts-a medial and a lateral nucleus differing in theirinputs, outputs, and cellular morphology. The medial component is related to the limbic system and serotonergic raphe, while the lateral nucleus is more interconnected with the basal ganglia and midbrain dopamine systems. These findings, which come from experiments mainly done on mammals, serve as a basis for comparison with other vertebrates. However, similar studies in other amniotes, such as reptiles, are few. To fill this gap in knowledge, two species of crocodiles were examined utilizing a variety of histological methods in various planes of section. The following results were obtained. First, the habenula was divided into medial and lateral parts based on its cytoarchitecture. Neurons in the medial habenula were small, were closely packed, and had a limited dendritic arbor characterized by unusual distal dendritic appendages, whereas neurons in the lateral habenula were larger, were more loosely packed, and had longer dendritic processes that were commonly beaded. Second, the stria medullaris, the major input to the habenula, was identified by its immunoreactivity to parvalbumin. Third, the fasciculus retroflexus (habenulointerpeduncular tract), the primary output of the habenula, was visualized by staining with acetylcholinesterase. Fourth, nuclei associated with the habenula, the subhabenular nuclei, have been identified and characterized. These features provide a means to recognize the major nuclei and tracts in the epithalamus in crocodiles and are likely applicable to other reptiles.

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by gradual loss of midbrain dopamine neurons, leading to impaired motor function. Preclinical studies have indicated cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) to be potential therapeutic molecules for the treatment of PD. CDNF was proven to be safe and well tolerated when tested in Phase I-II clinical trials in PD patients. Neuroprotective and neurorestorative effects of CDNF and MANF were demonstrated in animal models of PD, where they promoted the survival of dopamine neurons and improved motor function. However, biological roles of endogenous CDNF and MANF proteins in the midbrain dopamine system have been less clear. In addition to extracellular trophic activities, CDNF/MANF proteins function intracellularly in the endoplasmic reticulum (ER), where they modulate protein homeostasis and protect cells against ER stress by regulating the unfolded protein response (UPR). Here, our aim is to give an overview of the biology of endogenous CDNF and MANF in the brain dopamine system. We will discuss recent studies on CDNF and MANF knockout animal models, and effects of CDNF and MANF in preclinical models of PD. To elucidate possible roles of CDNF and MANF in human biology, we will review CDNF and MANF tissue expression patterns and regulation of CDNF/MANF levels in human diseases. Finally, we will discuss novel findings related to the molecular mechanism of CDNF and MANF action in ER stress, UPR, and inflammation, all of which are mechanisms potentially involved in the pathophysiology of PD.

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ9-tetrahydrocannabinol (Δ9-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% ofglutamatergic neurons, while PPARγ is expressed in ~60% ofGABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ9-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ9-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ9-THC-induced reduction in oICSS and Δ9-THC-inducedanxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ9-THC-induced hypoactivity and catalepsy but failed to alter Δ9-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.

An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models

The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson’s disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1’s transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD.

Dopamine-mediated striatal activity and function is enhanced in GlyRα2 knockout animals

The glycine receptor alpha 2 (GlyRα2) is a ligand-gated ion channel which upon activation induces a chloride conductance. Here, we investigated the role of GlyRα2 in dopamine-stimulated striatal cell activity and behavior. We show that depletion of GlyRα2 enhances dopamine-induced increases in the activity of putative dopamine D1 receptor-expressing striatal projection neurons, but does not alter midbrain dopamine neuron activity. We next show that the locomotor response to d-amphetamine is enhanced in GlyRα2 knockout animals, and that this increase correlates with c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the neuronal ensemble size in the striatum in response to D-amphetamine in GlyRα2 KO mice. Finally, we show enhanced appetitive conditioning in GlyRα2 KO animals that is likely due to increased motivation, but not changes in associative learning or hedonic response. Taken together, we show that GlyRα2 is an important regulator of dopamine-stimulated striatal activity and function.

Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons.

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which in addition to DA, glutamate or GABA are also released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. An emerging literature suggests that neuroligins, trans-synaptic cell adhesion molecules, regulate both DA connectivity and neurotransmission. However, the contribution of their major interaction partners, neurexins (Nrxns) is unexplored. Here we tested the hypothesis that Nrxns regulate DA neuron neurotransmission. Mice with conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) exhibited normal basic motor functions. However, they showed an impaired locomotor response to the psychostimulant amphetamine. In line with an alteration in DA neurotransmission, decreased levels of the membrane DA transporter (DAT) and increased levels of the vesicular monoamine transporter (VMAT2) were detected in the striatum of DAT::Nrxns KO mice, along with reduced activity-dependent DA release. Strikingly, electrophysiological recordings revealed an increase of GABA co-release from DA neuron axons in the striatum of these mice. Together, these findings suggest that Nrxns act as regulators of the functional connectivity of DA neurons.

Roles of octopamine neurons in the vertical lobe of the mushroom body for the execution of a conditioned response in cockroaches

Aminergic neurons mediate reward signals in mammals and insects. In crickets, we showed that blockade of synaptic transmission from octopamine neurons (OANs) impairs conditioning of an odor (conditioned stimulus, CS) with water or sucrose (unconditioned stimulus, US) and execution of a conditioned response (CR) to the CS. It has not yet been established, however, whether findings in crickets can be applied to other species of insects. In this study, we investigated the roles of OANs in conditioning of salivation, monitored by activities of salivary neurons, and in execution of the CR in cockroaches (Periplaneta americana). We showed that injection of epinastine (an OA receptor antagonist) into the head hemolymph impaired both conditioning and execution of the CR, in accordance with findings in crickets. Moreover, local injection of epinastine into the vertical lobes of the mushroom body (MB), the center for associative learning and control of the CR, impaired execution of the CR, whereas injection of epinastine into the calyces of the MB or the antennal lobes (primary olfactory centers) did not. We propose that OANs in the MB vertical lobes play critical roles in the execution of the CR in cockroaches. This is analogous to the fact that midbrain dopamine neurons govern execution of learned actions in mammals.

0039 Investigating the role of striatal dopamine in sleep and narcolepsy-cataplexy

Abstract Introduction Dopamine release in the striatum is known to govern reward, motor, and sleep behaviors. There also exists a link between pharmacological manipulation of dopamine receptors and cataplexy occurrence, yet the precise spatial and temporal dynamics of dopamine release in relation to cataplexy onset are not understood. In the present study, we evaluate dopamine release dynamics in orexin knockout (OX KO) mice during cataplexy and physiological behaviors. Methods OX KO mice were implanted with EEG/EMG electrodes, and dLight1.1 was expressed in the nucleus accumbens core (NAcc), shell (NAcSh), and dorsolateral striatum (DLS) to perform in vivo fiber photometry of dopamine release in freely-moving animals. In NAcc and NAcSh mice, ChrimsonR was retrogradely expressed in the ventral tegmental area (VTA), to allow for precise optogenetic control of midbrain dopamine projections to different regions of the striatum. We also expressed dLight1.1 in the NAcc of wildtype (WT) mice as a control. Three different stimulation parameters were used in independent recordings: phasic 20 Hz stimulation, phasic 10-40 Hz variable stimulation, and tonic 2 Hz stimulation. Results First, we show that while dopamine release in response to rewarding behaviors is muted in OX KO animals, there is no difference in dopamine release across sleep state transitions between OX KO and WT animals. Second, we demonstrate that there is a striking increase in dopamine release in both the NAcc and NAcSh, but not in the DLS, at the onset of cataplexy. This increase occurs independently of the behaviors that the animals were engaged in immediately prior to cataplexy, suggesting that the increase is characteristic of all cataplexy episodes. Finally, we find that while high frequency phasic stimulation did not affect cataplexy frequency, low frequency, tonic stimulation reduced both cataplexy and REM occurrence. Conclusion We show that there are differences in dopamine release in response to rewarding events, but not changes in sleep states, in OX KO and WT animals. We also identify dopamine release in the ventral striatum as a key node in cataplexy regulation, which helps to further our understanding of the limbic circuitry that underlies narcolepsy symptoms. Support (if any) University of Michigan Gilmore Award and Rackham Graduate Research Award.

Dopamine in the dorsal bed nucleus of stria terminalis signals Pavlovian sign-tracking and reward violations.

Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluorescent sensor technology and fiber photometry permit the measurement of dopamine binding correlates, which can divulge basic functions of dopamine signaling in non-striatal dopamine terminal regions, like the dorsal bed nucleus of the stria terminalis (dBNST). Here, we record GRABDA signals in the dBNST during a Pavlovian lever autoshaping task. We observe greater Pavlovian cue-evoked dBNST GRABDA signals in sign-tracking (ST) compared to goal-tracking/intermediate (GT/INT) rats and the magnitude of cue-evoked dBNST GRABDA signals decreases immediately following reinforcer-specific satiety. When we deliver unexpected rewards or omit expected rewards, we find that dBNST dopamine signals encode bidirectional reward prediction errors in GT/INT rats, but only positive prediction errors in ST rats. Since sign- and goal-tracking approach strategies are associated with distinct drug relapse vulnerabilities, we examined the effects of experimenter-administered fentanyl on dBNST dopamine associative encoding. Systemic fentanyl injections do not disrupt cue discrimination but generally potentiate dBNST dopamine signals. These results reveal multiple dBNST dopamine correlates of learning and motivation that depend on the Pavlovian approach strategy employed.

Medial Prefrontal Cortex to Medial Septum Pathway Activation Improves Cognitive Flexibility in Rats.

The medial prefrontal cortex (mPFC) is necessary for cognitive flexibility and projects to medial septum (MS). MS activation improves strategy switching, a common measure of cognitive flexibility, likely via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway (mPFC-MS) may be the mechanism by which the MS regulates strategy switching and DA neuron population activity. Male and female rats learned a complex discrimination strategy across 2 different training time points: a constant length (10 days) and a variable length that coincided with each rat meeting an acquisition-level performance threshold (males: 5.3 ± 0.3 days, females: 3.8 ± 0.3 days). We then chemogenetically activated or inhibited the mPFC-MS pathway and measured each rat's ability to inhibit the prior learned discrimination strategy and switch to a prior ignored discrimination strategy (strategy switching). Activation of the mPFC-MS pathway improved strategy switching after 10 days of training in both sexes. Inhibition of the pathway produced a modest improvement in strategy switching that was quantitatively and qualitatively different from pathway activation. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold training regimen. Activation, but not inhibition, of the mPFC-MS pathway bidirectionally regulated DA neuron activity in the ventral tegmental area and substantia nigra pars compacta, similar to general MS activation. This study presents a potential top-down circuit from the prefrontal cortex to the midbrain by which DA activity can be manipulated to promote cognitive flexibility.

Probing midbrain dopamine function in pediatric obsessive-compulsive disorder via neuromelanin-sensitive magnetic resonance imaging.

Obsessive-compulsive disorder (OCD) is an impairing psychiatric condition, which often onsets in childhood. Growing research highlights dopaminergic alterations in adult OCD, yet pediatric studies are limited by methodological constraints. This is the first study to utilize neuromelanin-sensitive MRI as a proxy for dopaminergic function among children with OCD. N = 135 youth (6-14-year-olds) completed high-resolution neuromelanin-sensitive MRI across two sites; n = 64 had an OCD diagnosis. N = 47 children with OCD completed a second scan after cognitive-behavioral therapy. Voxel-wise analyses identified that neuromelanin-MRI signal was higher among children with OCD compared to those without (483 voxels, permutation-corrected p = 0.018). Effects were significant within both the substania nigra pars compacta (p = 0.004, Cohen's d = 0.51) and ventral tegmental area (p = 0.006, d = 0.50). Follow-up analyses indicated that more severe lifetime symptoms (t = -2.72, p = 0.009) and longer illness duration (t = -2.22, p = 0.03) related to lower neuromelanin-MRI signal. Despite significant symptom reduction with therapy (p < 0.001, d = 1.44), neither baseline nor change in neuromelanin-MRI signal associated with symptom improvement. Current results provide the first demonstration of the utility of neuromelanin-MRI in pediatric psychiatry, specifically highlighting in vivo evidence for midbrain dopamine alterations in treatment-seeking youth with OCD. Neuromelanin-MRI likely indexes accumulating alterations over time, herein, implicating dopamine hyperactivity in OCD. Given evidence of increased neuromelanin signal in pediatric OCD but negative association with symptom severity, additional work is needed to parse potential longitudinal or compensatory mechanisms. Future studies should explore the utility of neuromelanin-MRI biomarkers to identify early risk prior to onset, parse OCD subtypes or symptom heterogeneity, and explore prediction of pharmacotherapy response.