Context-Dependent Multiplexing by Individual VTA Dopamine Neurons.

This study examined the effect of the acute and chronic systemic administration of (+/-)-8-Hydroxy-2-(Di-n-propylamino)Tetralin(8-OH-DPAT) on the number and firing pattern of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in anesthetized male rats. These parameters were measured using extracellular in vivo electrophysiology. A single s.c. injection of 0.01, 0.1, or 1 mg/kg of 8-OH-DPAT did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals (controls). The acute administration of 0.01 or 0.1 mg/kg of 8-OH-DPAT did not significantly alter, whereas the 1 mg/kg dose significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The acute administration of 8-OH-DPAT significantly increased the percentage of VTA DA neurons firing in a bursting pattern. In contrast, there was a significant decrease in the percentage of SNC DA neurons firing in a bursting pattern following the acute administration of 8-OH-DPAT. The number of spontaneously active SNC DA neurons was not significantly altered by the chronic s.c. administration of 8-OH-DPAT (0.01, 0.1, or 1 mg/kg s.c.) as compared to controls. However, the chronic s.c. administration of all doses of 8-OH-DPAT significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The i.v. administration of (+)-apomorphine (50 microg/kg) did not reverse the 8-OH-DPAT-induced decrease in the number of spontaneously active VTA DA neurons, suggesting that this effect is unlikely due to depolarization blockade. The percentage of VTA DA neurons exhibiting burst firing was significantly increased by 0.01 and 0.1 mg/kg, but significantly decreased by 1 mg/kg of 8-OH-DPAT. Overall, the systemic administration of 8-OH-DPAT preferentially affects the activity of spontaneously active A10 DA neurons in rats.

Dopamine (DA) neurons are thought to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

Sex-dependent emergence of prepubertal social dysfunction and augmented dopamine activity in a neurodevelopmental rodent model relevant for schizophrenia

ObjectChronic pain and negative emotions are often linked, and both can impact the reward circuit. The use of electroacupuncture (EA) has been found to regulate and improve these conditions. This study explores the potential mechanism of chronic pain relief by adding acupoints with emotional regulation effect to the basis of routine EA analgesia, to optimize the acupoint compatibility scheme of EA in the treatment of analgesia.MethodFor this study, 42 male Wistar rats were used. Recombinant adeno-associated viruses were used to label and regulate the activity of dopamine (DA) neurons. The rat model was established by complete Freund’s adjuvant (CFA). Lower limb electroacupuncture (LEA) was applied to the ST36 and BL60 acupoints. In addition, LEA + scalp EA (SEA) was given using the GV20 and GV24+ acupoints besides ST36 and BL60. To evaluate the pain threshold, we measured 50% paw withdrawal thresholds and thermal paw withdrawal latencies. Negative emotions were evaluated through the open field test, marble-burying test, sucrose preference test, and forced swimming test. Moreover, the conditional place preference test was conducted to measure the reward behavior in response to pain relief. Immunofluorescence staining, Western blotting, and qPCR were used to detect the activity of the VTADA-NAc reward circuit.ResultThe injection of CFA significantly lowered the pain threshold. As the pain persisted, the anxiety and depression-like behaviors escalated while the response to reward reduced. Meanwhile, the VTADA-NAc pathway was suppressed with pain chronification. However, activating DA neurons in VTA attenuated the effects induced by CFA. LEA could relieve chronic pain, negative emotions, and reward disorders, while also activating the VTADA-NAc pathway. In addition, LEA + SEA exhibited a more pronounced effect compared with LEA alone. Nevertheless, chemogenetic inhibition of DA neurons decreased the efficacy of LEA + SEA in the treatment of chronic pain and associated comorbidities.ConclusionAdding SEA to conventional LEA effectively alleviates negative emotions and chronic pain, potentially due to the activation of the VTADA-NAc reward neural circuit. Thus, LEA + SEA is a more effective treatment for hyperalgesia and associated negative emotions compared with LEA alone.

We recorded activity of dopamine (DA) neurons in the substantia nigra pars compacta in unrestrained mice while monitoring their movements with video tracking. Our approach allows an unbiased examination of the continuous relationship between single unit activity and behavior. Although DA neurons show characteristic burst firing following cue or reward presentation, as previously reported, their activity can be explained by the representation of actual movement kinematics. Unlike neighboring pars reticulata GABAergic output neurons, which can represent vector components of position, DA neurons represent vector components of velocity or acceleration. We found neurons related to movements in four directions—up, down, left, right. For horizontal movements, there is significant lateralization of neurons: the left nigra contains more rightward neurons, whereas the right nigra contains more leftward neurons. The relationship between DA activity and movement kinematics was found on both appetitive trials using sucrose and aversive trials using air puff, showing that these neurons belong to a velocity control circuit that can be used for any number of purposes, whether to seek reward or to avoid harm. In support of this conclusion, mimicry of the phasic activation of DA neurons with selective optogenetic stimulation could also generate movements. Contrary to the popular hypothesis that DA neurons encode reward prediction errors, our results suggest that nigrostriatal DA plays an essential role in controlling the kinematics of voluntary movements. We hypothesize that DA signaling implements gain adjustment for adaptive transition control, and describe a new model of the basal ganglia (BG) in which DA functions to adjust the gain of the transition controller. This model has significant implications for our understanding of movement disorders implicating DA and the BG.

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The hypothesis that midbrain dopamine (DA) neurons broadcast a reward prediction error (RPE) is among the great successes of computational neuroscience. However, recent results contradict a core aspect of this theory: specifically that the neurons convey a scalar, homogeneous signal. While the predominant family of extensions to the RPE model replicates the classic model in multiple parallel circuits, we argue that these models are ill suited to explain reports of heterogeneity in task variable encoding across DA neurons. Instead, we introduce a complementary 'feature-specific RPE' model, positing that individual ventral tegmental area DA neurons report RPEs for different aspects of an animal's moment-to-moment situation. Further, we show how our framework can be extended to explain patterns of heterogeneity in action responses reported among substantia nigra pars compacta DA neurons. This theory reconciles new observations of DA heterogeneity with classic ideas about RPE coding while also providing a new perspective of how the brain performs reinforcement learning in high-dimensional environments.

Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive. Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated. Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons. These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance. This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.

Dopamine (DA) neurons and GABA neurons of the substantia nigra (SN) promote distinct functions in the control of movement and have different firing properties and action potential (AP) waveforms. APs recorded from DA and GABA neurons differed in amplitude, maximal rate of rise, and duration. In addition, the threshold potential for APs was higher in DA neurons than in GABA neurons. The activation of voltage-gated Na(+) channels accounts largely for these differences as the application of a low concentration of the voltage-gated Na(+) channel blocker TTX had an effect on all of these parameters. We have examined functional properties of somatic Na(+) channels in nucleated patches isolated from DA and GABA neurons. Peak amplitudes of macroscopic Na(+) currents were smaller in DA neurons in comparison to those in GABA neurons. The mean peak Na(+) conductance density was 24.5 pS microm(-2) in DA neurons and almost twice as large, 41.6 pS microm(-2), in GABA neurons. The voltage dependence of Na(+) channel activation was not different between the two types of SN neurons. Na(+) channels in DA and GABA neurons, however, differed in the voltage dependence of inactivation, the mean mid-point potential of steady-state inactivation curve being more positive in DA neurons than in GABA neurons. The results suggest that specific Na(+) channel gating properties and Na(+) conductance densities in the somatic membrane of SN neurons may have consequences on synaptic signal integration in the soma of both types of neurons and on somatodendritic release of dopamine by DA neurons.

Can the apparent adaptation of dopamine neurons’ mismatch sensitivities be reconciled with their computation of reward prediction errors?

Stimulation of the prefrontal cortex (PFC) has been shown to have an excitatory influence on dopamine (DA) neurons. We report here that, under nonstimulated conditions, the activity of DA neurons in the ventral tegmental area (VTA) also covaries, on a subsecond timescale, with the activity of PFC cells. Thus, in 67% of VTA DA neurons recorded in chloral hydrate-anesthetized rats, the firing of the cell displayed a slow oscillation (SO) that was highly coherent with the activity of PFC neurons. The SO was suppressed by transections immediately caudal to the PFC or by intra-PFC infusion of tetrodotoxin, suggesting that it depends on inputs derived from the PFC. Unexpectedly, the SO in most VTA DA neurons was reversed in phase relative to PFC cell activity, suggesting that at least part of PFC information is transferred to DA neurons indirectly through inhibitory relay neurons. These results, together with those reported previously, suggest that the PFC can act through multiple pathways to exert both excitatory and inhibitory influences on DA neurons. The observed functional coupling between DA and PFC neurons further suggests that these pathways not only allow a bidirectional control of DA neurons by the PFC, but also enable action potential-dependent DA release to be coordinated, on a subsecond timescale, with glutamate release from PFC terminals. Further understanding of this coordinated activity may provide important new insights into brain functions and disorders thought to involve both VTA DA and PFC neurons.

Subsets of midbrain dopamine (DA) neurons express the vesicular glutamate transporter VGLUT2 and can release the excitatory neurotransmitter glutamate. VGLUT2+ DA neurons of the substantia nigra pars compacta (SNc) were shown to be more resistant to neurodegeneration in animal models of Parkinson's disease (PD). Additionally, there is evidence that VGLUT2+ DA neurons are enriched in the SNc of patients with PD, suggesting that VGLUT2 expression may confer resilience to DA neurons not only in animal models but also in the human disease. It remains unclear whether VGLUT2+ DA neurons are simply selected over VGLUT2- DA neurons during degeneration or whether VGLUT2 can also emerge de novo upon neuronal stress or injury. We employed pharmacological models of reversible parkinsonism to determine whether acute DA depletion or DA receptor antagonism would increase VGLUT2+ DA neurons in the SNc. Additionally, we isolated striatal synaptic vesicles from Parkinsonian mice to test how glutamate affected vesicular DA uptake. We found that acute depletion of DA or antagonism of D2 receptors sufficed to increase the fraction of DA neurons expressing VGLUT2, suggesting that VGLUT2 can emerge in DA neurons de novo. Increased VGLUT2 expression resulted in enhanced vesicular DA uptake in the presence of glutamate. Our work provides evidence that VGLUT2 expression is induced in DA neurons under conditions of hypodopaminergia or D2 receptor antagonism. VGLUT2 emergence in DA neurons may be a compensatory strategy when DA levels are low and/or DA receptor signalling is compromised.

Effects of estradiol and prolactin on incertohypothalamic dopaminergic neurons in the male rat

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine

6-Hydroxydopamine (6-OHDA)-induced loss of dopamine (DA) neurons has served to produce an animal model of DA neuron loss in Parkinson's disease. We report here the use of 6-OHDA to produce an in vitro model of this phenomena using dissociated cultures prepared from neonatal rat mesencephalon. Cultures were exposed to 6-OHDA (40-100 microm, 15 min) in an antioxidant medium, and DA and GABA neurons evaluated by immunocytochemistry. 6-OHDA induced morphological and biochemical signs of cell death in DA neurons within 3 h, followed by loss of tyrosine hydroxylase immunoreactive neurons within 2 days. In substantia nigra (SN) cultures, DA neurons were much more affected by 6-OHDA than were GABA neurons. In contrast, DA neurons from the ventral tegmental area were only lost at higher, non-specific concentrations of 6-OHDA. The effects of 6-OHDA on nigral DA neurons were blocked by inhibitors of high affinity DA transport and by z-DEVD-fmk (150 microm), a caspase inhibitor. Glial cell line-derived neurotrophic factor (GDNF) treatment reduced TUNEL labeling 3 h after 6-OHDA exposure, but did not prevent loss of DA neurons at 48 h. Thus, 6-OHDA can selectively destroy DA neurons in post-natal cultures of SN, acting at least in part by initiating caspase-dependent apoptosis, and this effect can be attenuated early but not late by GDNF.