Distributional coding of associative learning in discrete populations of midbrain dopamine neurons.

Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. Recent evidence suggests diversity in dopamine signaling, yet it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here, we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. Our findings show that reward information and behavioral parameters are not only heterogeneously encoded but also differentially distributed across populations of dopamine neurons. Retrograde tracing and fiber photometry suggest that populations of dopamine neurons projecting to different striatal regions convey distinct signals. These data, supported by computational modeling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate specialized roles of different striatal regions.

Association between RMTg Neuropeptide Genes and Negative Effect during Alcohol Withdrawal in Mice.

Alcohol use disorders (AUDs) frequently co-occur with negative mood disorders, such as anxiety and depression, exacerbating relapse through dopaminergic dysfunction. Stress-related neuropeptides play a crucial role in AUD pathophysiology by modulating dopamine (DA) function. The rostromedial tegmental nucleus (RMTg), which inhibits midbrain dopamine neurons and signals aversion, has been shown to increase ethanol consumption and negative emotional states during abstinence. Despite some stress-related neuropeptides acting through the RMTg to affect addiction behaviors, their specific roles in alcohol-induced contexts remain underexplored. This study utilized an intermittent voluntary drinking model in mice to induce negative effect behavior 24 h into ethanol (EtOH) abstinence (post-EtOH). It examined changes in pro-stress (Pnoc, Oxt, Npy) and anti-stress (Crf, Pomc, Avp, Orx, Pdyn) neuropeptide-coding genes and analyzed their correlations with aversive behaviors. We observed that adult male C57BL/6J mice displayed evident anxiety, anhedonia, and depression-like symptoms at 24 h post-EtOH. The laser-capture microdissection technique, coupled with or without retrograde tracing, was used to harvest total ventral tegmental area (VTA)-projecting neurons or the intact RMTg area. The findings revealed that post-EtOH consistently reduced Pnoc and Orx levels while elevating Crf levels in these neuronal populations. Notably, RMTg Pnoc and Npy levels counteracted ethanol consumption and depression severity, while Crf levels were indicative of the mice's anxiety levels. Together, these results underscore the potential role of stress-related neuropeptides in the RMTg in regulating the negative emotions related to AUDs, offering novel insights for future research.

Ultrasound Stimulation Attenuates CRS-Induced Depressive Behavior by Modulating Dopamine Release in the Prefrontal Cortex.

Depression is one of the most serious mental disorders affecting modern human life and is often caused by chronic stress. Dopamine system dysfunction is proposed to contribute to the pathophysiology of chronic stress, especially the ventral tegmental area (VTA) which mainly consists of dopaminergic neurons. Focused ultrasound stimulation (FUS) is a promising neuromodulation modality and multiple studies have demonstrated effective ultrasonic activation of cortical, subcortical, and related networks. However, the effects of FUS on the dopamine system and the potential link to chronic stress-induced depressive behaviors are relatively unknown. Here, we measured the effects of FUS targeting VTA on the improvement of depression-like behavior and evaluated the dopamine concentration in the downstream region - medial prefrontal cortex (mPFC). We found that targeting VTA FUS treatment alleviated chronic restraint stress (CRS) -induced anhedonia and despair behavior. Using an in vivo photometry approach, we analyzed the dopamine signal of mPFC and revealed a significant increase following the FUS, positively associated with the improvement of anhedonia behavior. FUS also protected the dopaminergic neurons in VTA from the damage caused by CRS exposure. Thus, these results demonstrated that targeting VTA FUS treatment significantly rescued the depressive-like behavior and declined dopamine level of mPFC induced by CRS. These beneficial effects of FUS might be due to protection in the DA neuron of VTA. Our findings suggest that FUS treatment could serve as a new therapeutic strategy for the treatment of stress-related disorders.

Local regulation of striatal dopamine: A diversity of circuit mechanisms for a diversity of behavioral functions?

Striatal dopamine governs a wide range of behavioral functions, yet local dopamine concentrations can be dissociated from somatic activity. Here, we discuss how dopamine's diverse roles in behavior may be driven by local circuit mechanisms shaping dopamine release. We first look at historical and recent work demonstrating that striatal circuits interact with dopaminergic terminals to either initiate the release of dopamine or modulate the release of dopamine initiated by spiking in midbrain dopamine neurons, with particular attention to GABAergic and cholinergic local circuit mechanisms. Then we discuss some of the first in vivo studies of acetylcholine-dopamine interactions in striatum and broadly discuss necessary future work in understanding the roles of midbrain versus striatal dopamine regulation.

Dopamine neuron activity encodes the length of upcoming contralateral movement sequences.

Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.

Heterogeneity of mesencephalic dopaminergic neurons: From molecular classifications, electrophysiological properties to functional connectivity.

The mesencephalic dopamine (DA) system is composed of neuronal subtypes that are molecularly and functionally distinct, are responsible for specific behaviors, and are closely associated with numerous brain disorders. Existing research has made significant advances in identifying the heterogeneity of mesencephalic DA neurons, which is necessary for understanding their diverse physiological functions and disease susceptibility. Moreover, there is a conflict regarding the electrophysiological properties of the distinct subsets of midbrain DA neurons. This review aimed to elucidate recent developments in the heterogeneity of midbrain DA neurons, including subpopulation categorization, electrophysiological characteristics, and functional connectivity to provide new strategies for accurately identifying distinct subtypes of midbrain DA neurons and investigating the underlying mechanisms of these neurons in various diseases.

An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences.

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu-VTAGABA-VTADA-ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.

PI4KIIIß-Mediated Phosphoinositides Metabolism Regulates Function of the VTA Dopaminergic Neurons and Depression-Like Behavior.

Phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), play a crucial role in controlling key cellular functions such as membrane and vesicle trafficking, ion channel, and transporter activity. Phosphatidylinositol 4-kinases (PI4K) are essential enzymes in regulating the turnover of phosphoinositides. However, the functional role of PI4Ks and mediated phosphoinositide metabolism in the central nervous system has not been fully revealed. In this study, we demonstrated that PI4KIIIß, one of the four members of PI4Ks, is an important regulator of VTA dopaminergic neuronal activity and related depression-like behavior of mice by controlling phosphoinositide turnover. Our findings provide new insights into possible mechanisms and potential drug targets for neuropsychiatric diseases, including depression. Both sexes were studied in basic behavior tests, but only male mice could be used in the social defeat depression model.

Glutamate inputs send prediction error of reward, but not negative value of aversive stimuli, to dopamine neurons.

Midbrain dopamine neurons are thought to signal reward prediction errors (RPEs), but the mechanisms underlying RPE computation, particularly the contributions of different neurotransmitters, remain poorly understood. Here, we used a genetically encoded glutamate sensor to examine the pattern of glutamate inputs to dopamine neurons in mice. We found that glutamate inputs exhibit virtually all of the characteristics of RPE rather than conveying a specific component of RPE computation, such as reward or expectation. Notably, whereas glutamate inputs were transiently inhibited by reward omission, they were excited by aversive stimuli. Opioid analgesics altered dopamine negative responses to aversive stimuli into more positive responses, whereas excitatory responses of glutamate inputs remained unchanged. Our findings uncover previously unknown synaptic mechanisms underlying RPE computations; dopamine responses are shaped by both synergistic and competitive interactions between glutamatergic and GABAergic inputs to dopamine neurons depending on valences, with competitive interactions playing a role in responses to aversive stimuli.

State and rate-of-change encoding in parallel mesoaccumbal dopamine pathways.

The nervous system uses fast- and slow-adapting sensory detectors in parallel to enable neuronal representations of external states and their temporal dynamics. It is unknown whether this dichotomy also applies to internal representations that have no direct correlation in the physical world. Here we find that two distinct dopamine (DA) neuron subtypes encode either a state or its rate-of-change. In mice performing a reward-seeking task, we found that the animal's behavioral state and rate-of-change were encoded by the sustained activity of DA neurons in medial ventral tegmental area (VTA) DA neurons and transient activity in lateral VTA DA neurons, respectively. The neural activity patterns of VTA DA cell bodies matched DA release patterns within anatomically defined mesoaccumbal pathways. Based on these results, we propose a model in which the DA system uses two parallel lines for proportional-differential encoding of a state variable and its temporal dynamics.

Dopamine regulates attitude toward risk.

Specific brain pathways can lower or raise the willingness of monkeys to take risks.

Sensory Cues Potentiate VTA Dopamine Mediated Reinforcement.

Sensory cues are critical for shaping decisions and invigorating actions during reward seeking. Dopamine neurons in the ventral tegmental area (VTA) are central in this process, supporting associative learning in Pavlovian and instrumental settings. Studies of intracranial self-stimulation (ICSS) behavior, which show that animals will work hard to receive stimulation of dopamine neurons, support the notion that dopamine transmits a reward or value signal to support learning. Recent studies have begun to question this, however, emphasizing dopamine's value-free functions, leaving its contribution to behavioral reinforcement somewhat muddled. Here, we investigated the role of sensory stimuli in dopamine-mediated reinforcement, using an optogenetic ICSS paradigm in tyrosine hydroxylase (TH)-Cre rats. We find that while VTA dopamine neuron activation in the absence of explicit external cues is sufficient to maintain robust self-stimulation, the presence of cues dramatically potentiates ICSS behavior. Our results support a framework where dopamine can have some base value as a reinforcer, but the impact of this signal is modulated heavily by the sensory learning context.

Combining physical & cognitive training with iPSC-derived dopaminergic neuron transplantation promotes graft integration & better functional outcome in parkinsonian marmosets.

Parkinson's disease (PD) is a relentlessly progressive and currently incurable neurodegenerative disease with significant unmet medical needs. Since PD stems from the degeneration of midbrain dopaminergic (DA) neurons in a defined brain location, PD patients are considered optimal candidates for cell replacement therapy. Clinical trials for cell transplantation in PD are beginning to re-emerge worldwide with a new focus on induced pluripotent stem cells (iPSCs) as a source of DA neurons since they can be derived from adult somatic cells and produced in large quantities under current good manufacturing practices. However, for this therapeutic strategy to be realized as a viable clinical option, fundamental translational challenges need to be addressed including the manufacturing process, purity and efficacy of the cells, the method of delivery, the extent of host reinnervation and the impact of patient-centered adjunctive interventions. In this study we report on the impact of physical and cognitive training (PCT) on functional recovery in the nonhuman primate (NHP) model of PD after cell transplantation. We observed that at 6 months post-transplant, the PCT group returned to normal baseline in their daily activity measured by actigraphy, significantly improved in their sensorimotor and cognitive tasks, and showed enhanced synapse formation between grafted cells and host cells. We also describe a robust, simple, efficient, scalable, and cost-effective manufacturing process of engraftable DA neurons derived from iPSCs. This study suggests that integrating PCT with cell transplantation therapy could promote optimal graft functional integration and better outcome for patients with PD.

Progress in direct reprogramming of dopaminergic cell replacement therapy.

Parkinson's disease (PD) is a gradual neurodegenerative disease. While drug therapy and surgical treatments have been the primary means of addressing PD, they do not offer a cure, and the risks associated with surgical treatment are high. Recent advances in cell reprogramming have given rise to new prospects for the treatment of Parkinson's disease (PD), with induced pluripotent stem cells (iPSCs), induced dopamine neurons (iDNs), and induced neural stem cells (iNSCs) being created. These cells can potentially be used in the treatment of Parkinson's disease. On the other hand, this article emphasizes the limits of iPSCs and iNSCs in the context of Parkinson's disease treatment, as well as approaches for direct reprogramming of somatic cells into iDNs. The paper will examine the benefits and drawbacks of directly converting somatic cells into iDNs.

An excitatory projection from the basal forebrain to the ventral tegmental area that underlies anorexia-like phenotypes.

Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF → VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of anxiety, all hallmarks of typical anorexia symptoms. Importantly, activation of BF glutamatergic terminals in the VTA reduced dopamine release in the nucleus accumbens. Collectively, our results point to overactivation of the glutamatergic BF → VTA circuit as a potential cause of anorexia-like phenotypes involving reduced dopamine release.

An Ascending Excitatory Circuit from the Dorsal Raphe for Sensory Modulation of Pain.

The dorsal raphe nucleus (DRN) is an important nucleus in pain regulation. However, the underlying neural pathway and the function of specific cell types remain unclear. Here, we report a previously unrecognized ascending facilitation pathway, the DRN to the mesoaccumbal dopamine (DA) circuit, for regulating pain. Chronic pain increased the activity of DRN glutamatergic, but not serotonergic, neurons projecting to the ventral tegmental area (VTA) (DRNGlu-VTA) in male mice. The optogenetic activation of DRNGlu-VTA circuit induced a pain-like response in naive male mice, and its inhibition produced an analgesic effect in male mice with neuropathic pain. Furthermore, we discovered that DRN ascending pathway regulated pain through strengthened excitatory transmission onto the VTA DA neurons projecting to the ventral part of nucleus accumbens medial shell (vNAcMed), thereby activated the mesoaccumbal DA neurons. Correspondingly, optogenetic manipulation of this three-node pathway bilaterally regulated pain behaviors. These findings identified a DRN ascending excitatory pathway that is crucial for pain sensory processing, which can potentially be exploited toward targeting pain disorders.

Reduction in the activity of VTA/SNc dopaminergic neurons underlies aging-related decline in novelty seeking.

Curiosity, or novelty seeking, is a fundamental mechanism motivating animals to explore and exploit environments to improve survival, and is also positively associated with cognitive, intrapersonal and interpersonal well-being in humans. However, curiosity declines as humans age, and the decline even positively predicts the extent of cognitive decline in Alzheimer's disease patients. Therefore, determining the underlying mechanism, which is currently unknown, is an urgent task for the present aging society that is growing at an unprecedented rate. This study finds that seeking behaviors for both social and inanimate novelties are compromised in aged mice, suggesting that the aging-related decline in curiosity and novelty-seeking is a biological process. This study further identifies an aging-related reduction in the activity (manifesting as a reduction in spontaneous firing) of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Finally, this study establishes that this reduction in activity causally underlies the aging-related decline in novelty-seeking behaviors. This study potentially provides an interventional strategy for maintaining high curiosity in the aged population, i.e., compensating for the reduced activity of VTA/SNc dopaminergic neurons, enabling the aged population to cope more smoothly with the present growing aging society, physically, cognitively and socioeconomically.

Cell type specificity for circuit output in the midbrain dopaminergic system.

Midbrain dopaminergic neurons are a relatively small group of neurons in the mammalian brain controlling a wide range of behaviors. In recent years, increasingly sophisticated tracing, imaging, transcriptomic, and machine learning approaches have provided substantial insights into the anatomical, molecular, and functional heterogeneity of dopaminergic neurons. Despite this wealth of new knowledge, it remains unclear whether and how the diverse features defining dopaminergic subclasses converge to delineate functional ensembles within the dopaminergic system. Here, we review recent studies investigating various aspects of dopaminergic heterogeneity and discuss how development, behavior, and disease influence subtype characteristics. We then outline what further approaches could be pursued to gain a more inclusive picture of dopaminergic diversity, which could be crucial to understanding the functional architecture of this system.

Chronic high-sugar diet in adulthood protects Caenorhabditis elegans from 6-OHDA-induced dopaminergic neurodegeneration.

BACKGROUND: Diets high in saturated fat and sugar, termed "Western diets," have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high-sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high-sugar diets and dopaminergic neurodegeneration. RESULTS: Adult high-glucose and high-fructose diets, or exposure from day 1 to 5 of adulthood, led to increased lipid content, shorter lifespan, and decreased reproduction. However, in contrast to previous reports, we found that adult chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high-sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting downregulation of the dopamine reuptake transporter dat-1 that could result in decreased 6-OHDA uptake. CONCLUSIONS: Our work uncovers a neuroprotective role for high-sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions.

Top-down circuitry from the anterior insular cortex to VTA dopamine neurons modulates reward-related memory.

The insular cortex (IC) has been linked to the processing of interoceptive and exteroceptive signals associated with addictive behavior. However, whether the IC modulates the acquisition of drug-related affective states by direct top-down connectivity with ventral tegmental area (VTA) dopamine neurons is unknown. We found that photostimulation of VTA terminals of the anterior insular cortex (aIC) induces rewarding contextual memory, modulates VTA activity, and triggers dopamine release within the VTA. Employing neuronal recordings and neurochemical and transsynaptic tagging techniques, we disclose the functional top-down organization tagging the aIC pre-synaptic neuronal bodies and identifying VTA recipient neurons. Furthermore, systemic administration of amphetamine altered the VTA excitability of neurons modulated by the aIC projection, where photoactivation enhances, whereas photoinhibition impairs, a contextual rewarding behavior. Our study reveals a key circuit involved in developing and retaining drug reward-related contextual memory, providing insight into the neurobiological basis of addictive behavior and helping develop therapeutic addiction strategies.