VTA-DA Neurons Research Articles

Distinct Neuromodulatory Effects of Endogenous Orexin and Dynorphin Corelease on Projection-Defined Ventral Tegmental Dopamine Neurons.

Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues, and circuit-specific signaling drives different aspects of motivated behavior. Orexin (ox; also known as hypocretin) and dynorphin (dyn) are coexpressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the coreleased peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LHox/dyn neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregate based on VTADA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch-clamp electrophysiology in male and female orexincre mice, we showed a diverse response of LHox/dyn optical stimulation on VTADA neuronal firing, which is not mediated by fast transmitter release and is blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA-projecting VTADA neurons, optical stimulation of LHox/dyn inputs in the VTA bidirectionally affects firing of either lAcbSh- or mAchSh-projecting VTADA neurons. These findings indicate that LHox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.

Dopamine Release in the Nucleus Accumbens Core Encodes the General Excitatory Components of Learning.

Dopamine release in the nucleus accumbens core (NAcC) is generally considered to be a proxy for phasic firing of the ventral tegmental area dopamine (VTADA) neurons. Thus, dopamine release in NAcC is hypothesized to reflect a unitary role in reward prediction error signaling. However, recent studies reveal more diverse roles of dopamine neurons, which support an emerging idea that dopamine regulates learning differently in distinct circuits. To understand whether the NAcC might regulate a unique component of learning, we recorded dopamine release in NAcC while male rats performed a backward conditioning task where a reward is followed by a neutral cue. We used this task because we can delineate different components of learning, which include sensory-specific inhibitory and general excitatory components. Furthermore, we have shown that VTADA neurons are necessary for both the specific and general components of backward associations. Here, we found that dopamine release in NAcC increased to the reward across learning while reducing to the cue that followed as it became more expected. This mirrors the dopamine prediction error signal seen during forward conditioning and cannot be accounted for temporal-difference reinforcement learning. Subsequent tests allowed us to dissociate these learning components and revealed that dopamine release in NAcC reflects the general excitatory component of backward associations, but not their sensory-specific component. These results emphasize the importance of examining distinct functions of different dopamine projections in reinforcement learning.

NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA.

Major depressive disorder (MDD) is characterized by diverse debilitating symptoms that include loss of motivation and anhedonia. If multiple medications, psychotherapy, and electroconvulsive therapy fail in some patients with MDD, their condition is then termed treatment-resistant depression (TRD). MDD can be associated with abnormalities in the reward-system-dopaminergic mesolimbic pathway, in which the nucleus accumbens (NAc) and ventral tegmental area (VTA) play major roles. Deep brain stimulation (DBS) applied to the NAc alleviates the depressive symptoms of MDD. However, the mechanism underlying the effects of this DBS has remained elusive. In this study, using the chronic unpredictable mild stress (CUMS) mouse model, we investigated the behavioral and neurobiological effects of NAc-DBS on the multidimensional depression-like phenotypes induced by CUMS by integrating behavioral, in vivo microdialysis coupled with high-performance liquid chromatography-electrochemical detector (HPLC-ECD), calcium imaging, pharmacological, and genetic manipulation methods in freely moving mice. We found that long-term and repeated, but not single, NAc-DBS induced robust antidepressant responses in CUMS mice. Moreover, even a single trial NAc-DBS led to the elevation of the γ-aminobutyric acid (GABA) neurotransmitter, accompanied by the increase in dopamine (DA) neuron activity in the VTA. Both the inhibition of the GABAA receptor activity and knockdown of the GABAA-α1 gene in VTA-GABA neurons blocked the antidepressant effect of NAc-DBS in CUMS mice. Our results showed that NAc-DBS could disinhibit VTA-DA neurons by regulating the level of GABA and the activity of VTA-GABA in the VTA and could finally correct the depression-like behaviors in the CUMS mouse model.

The design of self-healing memristive network circuit based on VTA DA neurons and its application

This paper proposes a self-healing memristive network circuit, which simulates the resilience mechanism of VTA DA neurons. The proposed memristive network circuit mainly consists of four modules: input (synapse) module, damage detection module, threshold trigger module and negative feedback module. The input module is composed of a memristive synaptic circuit, which can react to a harmful initial input rather than a normal initial input. Apart from reacting to initial input, the input module also can receive a feedback signal released by the negative feedback module, and the process of receiving feedback signal is the key of realizing the self-healing function. The damage detection module can output a low level pulse that acts as an input signal of the threshold trigger module when the harmful initial input exists. The threshold trigger module will activate the negative feedback module when the trigger point which corresponds to the positive threshold voltage of memristor is reached. As the last module of the self-healing function, the negative feedback module can transmit the feedback signal, also be called a repairing signal, to the damaged memristor of the input module. The PSPICE simulation results indicate that the proposed memristive network circuit can realize the self-healing function which corresponds to the resilience mechanism of the VTA DA neurons. Meanwhile, when the proposed memristive network circuit has been applied to the damaged electronic machines or robots, the self-healing function of it can make the machines be reusable.

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.

Scalp electroacupuncture targeting the VTADA neurons to relieve negative emotions and promote the alleviation of chronic pain.

Chronic 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. For 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. The 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. Adding 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.

The PFC-LH-VTA pathway contributes to social deficits in IRSp53-mutant mice

Dopamine (DA) neurons in the ventral tegmental area (VTA) promote social brain functions by releasing DA onto nucleus accumbens neurons, but it remains unclear how VTA neurons communicate with cortical neurons. Here, we report that the medial prefrontal cortex (mPFC)-lateral hypothalamus (LH)-VTA pathway contributes to social deficits in mice with IRSp53 deletion restricted to cortical excitatory neurons (Emx1-Cre;Irsp53fl/fl mice). LH-projecting mutant mPFC neurons display abnormally increased excitability involving decreased potassium channel gene expression, leading to excessive excitatory synaptic input to LH-GABA neurons. A circuit-specific IRSp53 deletion in LH-projecting mPFC neurons also increases neuronal excitability and induces social deficits. LH-GABA neurons with excessive mPFC excitatory synaptic input show a compensatory decrease in excitability, weakening the inhibitory LHGABA-VTAGABA pathway and subsequently over-activating VTA-GABA neurons and over-inhibiting VTA-DA neurons. Accordingly, optogenetic activation of the LHGABA-VTAGABA pathway improves social deficits in Emx1-Cre;Irsp53fl/fl mice. Therefore, the mPFC-LHGABA-VTAGABA-VTADA pathway contributes to the social deficits in Emx1-Cre;Irsp53fl/fl mice.

Overlapping representations of food and social stimuli in mouse VTA dopamine neurons

Dopamine neurons of the ventral tegmental area (VTADA) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear whether the same or different VTADA neurons encode these different stimuli. To address this question, we performed two-photon calcium imaging in mice presented with food and conspecifics and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience further increased the proportion of neurons that respond to both stimuli, implying that increasing motivation for one stimulus increases overlap. In addition, single-nucleus RNA sequencing revealed significant co-expression of feeding- and social-hormone-related genes in individual VTADA neurons. Taken together, our functional and transcriptional data suggest overlapping VTADA populations underlie food and social motivation.

Modulation of dopamine from ventral tegmental area neurons by the LC-REM-OFF and PPT-REM-ON neurons in REMS regulation in freely moving rats

The role of dopamine (DA)-ergic neurons in ventral tegmental area (VTA) in schizophrenia, depression, hallucinations have been extensively studied. Rapid eye movement sleep (REMS), the closest objective correlate of dream and hallucination, is disrupted during these psychological dysfunctions; however, it was unknown if there is any common neuronal substrate for their regulation. Interactions among locus coeruleus (LC) REM-OFF and pedunculopontine tegmentum (PPT) REM-ON neurons have been reported to regulate REMS in health and diseases. Recently we have reported that PPT neurons modulate VTA and REMS. However, although VTA-DA neurons receive projections from LC and PPT, their role in REMS regulation was unclear. We proposed that the LC and PPT might intermittently modulate VTA-DA neurons and modulate REMS. Male Wistar rats were surgically prepared and electrophysiological wakefulness-sleep-REMS recorded in chronic freely moving condition. We employed RNAi induced downregulation of tyrosine hydroxylase (TH) to evaluate the role of VTA-DA in regulating REMS. We observed that TH-knockdown in VTA decreased REMS in experimental rats, which returned to baseline upon PPT stimulation. Thus, VTA-DA neurons are activated by the REM-ON neurons to modulate REMS, the closest objectively recordable correlate of dreams. In these animals, LC stimulation altered Non-REMS and waking. Based on the findings we have discussed the role of VTA neurochemical circuitry in REMS regulation and their possible implications with REMS-associated dreaming and hallucination in health and diseases.

Degeneracy and stability in neural circuits of dopamine and serotonin neuromodulators: A theoretical consideration.

Degenerate neural circuits perform the same function despite being structurally different. However, it is unclear whether neural circuits with interacting neuromodulator sources can themselves degenerate while maintaining the same neuromodulatory function. Here, we address this by computationally modeling the neural circuits of neuromodulators serotonin and dopamine, local glutamatergic and GABAergic interneurons, and their possible interactions, under reward/punishment-based conditioning tasks. The neural modeling is constrained by relevant experimental studies of the VTA or DRN system using, e.g., electrophysiology, optogenetics, and voltammetry. We first show that a single parsimonious, sparsely connected neural circuit model can recapitulate several separate experimental findings that indicated diverse, heterogeneous, distributed, and mixed DRNVTA neuronal signaling in reward and punishment tasks. The inability of this model to recapitulate all observed neuronal signaling suggests potentially multiple circuits acting in parallel. Then using computational simulations and dynamical systems analysis, we demonstrate that several different stable circuit architectures can produce the same observed network activity profile, hence demonstrating degeneracy. Due to the extensive D2-mediated connections in the investigated circuits, we simulate the D2 receptor agonist by increasing the connection strengths emanating from the VTA DA neurons. We found that the simulated D2 agonist can distinguish among sub-groups of the degenerate neural circuits based on substantial deviations in specific neural populations' activities in reward and punishment conditions. This forms a testable model prediction using pharmacological means. Overall, this theoretical work suggests the plausibility of degeneracy within neuromodulator circuitry and has important implications for the stable and robust maintenance of neuromodulatory functions.

Dopamine errors drive excitatory and inhibitory components of backward conditioning in an outcome-specific manner

For over two decades, phasic activity in midbrain dopamine neurons was considered synonymous with the prediction error in temporal-difference reinforcement learning.1-4 Central to this proposal is the notion that reward-predictive stimuli become endowed with the scalar value of predicted rewards. When these cues are subsequently encountered, their predictive value is compared to the value of the actual reward received, allowing for the calculation of prediction errors.5,6 Phasic firing of dopamine neurons was proposed to reflect this computation,1,2 facilitating the backpropagation of value from the predicted reward to the reward-predictive stimulus, thus reducing future prediction errors. There are two critical assumptions of this proposal: (1) that dopamine errors can only facilitate learning about scalar value and not more complex features of predicted rewards, and (2) that the dopamine signal can only be involved in anticipatory cue-reward learning in which cues or actions precede rewards. Recent work7-15 has challenged the first assumption, demonstrating that phasic dopamine signals across species are involved in learning about more complex features of the predicted outcomes, in a manner that transcends this value computation. Here, we tested the validity of the second assumption. Specifically, we examined whether phasic midbrain dopamine activity would be necessary for backward conditioning-when a neutral cue reliably follows a rewarding outcome.16-20 Using a specific Pavlovian-to-instrumental transfer (PIT) procedure,21-23 we show rats learn both excitatory and inhibitory components of a backward association, and that this association entails knowledge of the specific identity of the reward and cue. We demonstrate that brief optogenetic inhibition of VTADA neurons timed to the transition between the reward and cue reduces both of these components of backward conditioning. These findings suggest VTADA neurons are capable of facilitating associations between contiguously occurring events, regardless of the content of those events. We conclude that these data may be in line with suggestions that the VTADA error acts as a universal teaching signal. This may provide insight into why dopamine function has been implicated in myriad psychological disorders that are characterized by very distinct reinforcement-learning deficits.

Modified viral-genetic mapping reveals local and global connectivity relationships of ventral tegmental area dopamine cells.

Dopamine cells in the ventral tegmental area (VTADA) are critical for a variety of motivated behaviors. These cells receive synaptic inputs from over 100 anatomically defined brain regions, which enables control from a distributed set of inputs across the brain. Extensive efforts have been made to map inputs to VTA cells based on neurochemical phenotype and output site. However, all of these studies have the same fundamental limitation that inputs local to the VTA cannot be properly assessed due to non-Cre-dependent uptake of EnvA-pseudotyped virus. Therefore, the quantitative contribution of local inputs to the VTA, including GABAergic, DAergic, and serotonergic, is not known. Here, I used a modified viral-genetic strategy that enables examination of both local and long-range inputs to VTADA cells in mice. I found that nearly half of the total inputs to VTADA cells are located locally, revealing a substantial portion of inputs that have been missed by previous analyses. The majority of inhibition to VTADA cells arises from the substantia nigra pars reticulata, with large contributions from the VTA and the substantia nigra pars compacta. In addition to receiving inputs from VTAGABA neurons, DA neurons are connected with other DA neurons within the VTA as well as the nearby retrorubal field. Lastly, I show that VTADA neurons receive inputs from distributed serotonergic neurons throughout the midbrain and hindbrain, with the majority arising from the dorsal raphe. My study highlights the importance of using the appropriate combination of viral-genetic reagents to unmask the complexity of connectivity relationships to defined cells in the brain.

Distinct limbic dopamine regulation across olfactory-tubercle subregions through integration of in vivo fast-scan cyclic voltammetry and optogenetics.

The olfactory tubercle (OT), an important component of the ventral striatum and limbic system, is involved in multi-sensory integration of reward-related information in the brain. However, its functional roles are often overshadowed by the neighboring nucleus accumbens. Increasing evidence has highlighted that dense dopamine (DA) innervation of the OT from the ventral tegmental area (VTA) is implicated in encoding reward, natural reinforcers, and motivated behaviors. Recent studies have further suggested that OT subregions may have distinct roles in these processes due to their heterogeneous DA transmission. Currently, very little is known about regulation (release and clearance) of extracellular DA across OT subregions due to its limited anatomical accessibility and proximity to other DA-rich brain regions, making it difficult to isolate VTA-DA signaling in the OT with conventional methods. Herein, we characterized heterogeneous VTA-DA regulation in the medial (m) and lateral (l) OT in "wild-type," urethane-anesthetized rats by integrating in vivo fast-scan cyclic voltammetry with cell-type specific optogenetics to stimulate VTA-DA neurons. Channelrhodopsin-2 was selectively expressed in the VTA-DA neurons of wild-type rats and optical stimulating parameters were optimized to determine VTA-DA transmission across the OT. Our anatomical, neurochemical, and pharmacological results show that VTA-DA regulation in the mOT is less dependent on DA transporters and has greater DA transmission than the lOT. These findings establish the OT as a unique, compartmentalized structure and will aid in future behavioral characterization of the roles of VTA-DA signaling in the OT subregions in reward, drug addiction, and encoding behavioral outputs necessary for survival.

Dopaminergic Projection from Ventral Tegmental Area to Substantia Nigra Pars Reticulata Mediates Chronic Social Defeat Stress-Induced Hypolocomotion.

Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.

Restoring VTA DA neurons excitability accelerates emergence from sevoflurane general anesthesia of anxiety state

Preoperative anxiety is common and often comes with a higher probability of worse recovery. However, the neurological mechanism of the effect of preoperative anxiety on general anesthesia and subsequent awakening remains unknown. In this study, we report an anxious state results in delayed awakening in anxiety model mice from sevoflurane general anesthesia. More profound inhibition of DA neurons in the VTA contributes to delayed awakening. Optogenetic stimulation of VTA DA neurons can reverse the delay. The results indicate that VTA DA neurons may be involved in the delay in awakening from general anesthesia caused by anxiety.

Dopaminergic Projections From the Ventral Tegmental Area to the Nucleus Accumbens Modulate Sevoflurane Anesthesia in Mice.

The role of the dopaminergic pathway in general anesthesia and its potential mechanisms are still unknown. In this study, we usedc-Fos staining combined with calcium fiber photometry recording to explore the activity of ventral tegmental area (VTA) dopaminergic neurons(VTA-DA) and nucleus accumbens (NAc) neurons during sevoflurane anesthesia. A genetically encoded dopamine (DA) sensor was used to investigate thefunction of the NAc in sevoflurane anesthesia. Chemogenetics and optogenetics were used to explore the role of the VTA-DA in sevofluraneanesthesia. Electroencephalogram (EEG) spectra, time of loss of righting reflex (LORR) and recovery of righting reflex (RORR) were recorded asassessment indicators. We found that VTA-DA and NAc neurons were inhibited during the induction period and were activated during the recoveryperiod of sevoflurane anesthesia. The fluorescence signals of dopamine decreased in the induction of and increased in the emergence from sevoflurane anesthesia.Activation of VTA-DA and the VTADA-NAc pathway delayed the induction and facilitated the emergence accompanying with thereduction of delta band and the augmentation of the gamma band. These data demonstrate that VTA-DA neurons play a critical role in modulating sevofluraneanesthesia via the VTADA-NAc pathway.

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress.

Stressful events, similar to abused drugs, significantly affect the homeostatic balance of the catecholamine brain systems while activating compensation mechanisms to restore balance. In detail, norepinephrine (NE)- and dopamine (DA)-containing neurons within the locus coeruleus (LC) and ventral tegmental area (VTA), are readily and similarly activated by psychostimulants and stressful events involving neural processes related to perception, reward, cognitive evaluation, appraisal, and stress-dependent hormonal factors. Brain catecholamine response to stress results in time-dependent regulatory processes involving mesocorticolimbic circuits and networks, where LC-NE neurons respond more readily than VTA-DA neurons. LC-NE projections are dominant in controlling the forebrain DA-targeted areas, such as the nucleus accumbens (NAc) and medial pre-frontal cortex (mPFC). Heavy and persistent coping demand could lead to sustained LC-NE and VTA-DA neuronal activity, that, when persisting chronically, is supposed to alter LC-VTA synaptic connections. Increasing evidence has been provided indicating a role of autophagy in modulating DA neurotransmission and synaptic plasticity. This alters behavior, and emotional/cognitive experience in response to drug abuse and occasionally, to psychological stress. Thus, relevant information to address the role of stress and autophagy can be drawn from psychostimulants research. In the present mini-review we discuss the role of autophagy in brain catecholamine response to stress and its dysregulation. The findings here discussed suggest a crucial role of regulated autophagy in the response and adaptation of LC-NE and VTA-DA systems to stress.

Morphine selectively disinhibits glutamatergic input from mPFC onto dopamine neurons of VTA, inducing reward

Ventral tegmental area (VTA) dopamine (DA) neurons presynaptic glutamate release plays a very important role in the mechanism of morphine. Previously, a study from our lab found that morphine disinhibited glutamatergic input onto the VTA-DA neurons, which was an important mechanism for the morphine-induced increase in the VTA-DA neuron firing and related behaviors (Chen et al., 2015). However, what source of glutamatergic inputs is disinhibited by morphine remains to be elucidated. Using optogenetic strategy combined with whole-cell patch-clamp, qRT-PCR, immunofluorescence and chemical genetic approach combined with behavioral methods, our results show that: 1) morphine promotes glutamate release from glutamatergic terminals of medial prefrontal cortex (mPFC) neurons projecting to VTA-DA neurons but does not on those from glutamatergic terminals of the lateral hypothalamus (LH) neurons projecting to VTA-DA neurons; 2) different response of glutamatergic neurons projecting to VTA-DA neurons from the mPFC or the LH to morphine is related to the expression of GABAB receptors at terminals of these neurons; 3) inhibition of projection neurons from the mPFC to the VTA significantly reduces morphine-induced locomotor activity increase and conditioned place preference but inhibition of projection neurons from the LH to the VTA does not. These results suggest that morphine selectively promotes glutamate release of the glutamatergic input from mPFC onto VTA-DA neurons by removing the inhibition of the GABAB receptors in this glutamatergic input from mPFC.

A Dopamine-Gated Nucleus Accumbens Circuit for Cognitive Map Reification

Animals navigate environment based on cognitive map built upon spatial cues and desired outcomes. However, how the goal representation stems from spatial information and outcomes, and its causal role in action control, remain elusive. Here we show that ‘where-to-escape’ relies on the cognitive map formulated by shelter experience. Dopamine (DA) neurons in the ventral tegmental area (VTA) exhibit valence encodings and the phasic burst stimulations of VTADA neurons sufficiently generate latent goal memory. Converging DA and excitatory inputs from VTA and hippocampus (HPC), respectively, onto the nucleus accumbens (NAc) is required for goal memory formation, integrating spatial value with the place. Tracking cellular dynamics of NAc neurons reveals emerging ensembles representing shelter positions. Targeting functionally-selective neuronal ensemble guides movements towards the goal location, regardless of the animal’s position. Thus, our findings reveal a neural basis of goal memory-to-action instantiation, demonstrating the feasibility of cognitive action tracing in space and time.

H‐current blocker (ZD 7288) reduces firing patterns on putative dopaminergic neurons of the Ventral Tegmental Area

The hyperpolarization‐activated cation current (H‐current) is a major determinant of neuronal intrinsic excitability in various cells including dopaminergic neurons of the Ventral Tegmental Area (VTA DA). In contrast to other cellular conductances, the H‐current activates through hyperpolarizing voltage steps to potentials negative to −55mV and depolarizes the membrane potential. We explored through in vivo anesthetized single unit extracellular electrophysiology the contribution of the H‐current on VTA DA neurons spontaneous firing patterns in naïve rats. A key feature of evaluating spontaneous excitability is the detection of bursting activity. Bursting is defined as trains of two or more spikes occurring within a short interval and followed by a prolonged period of inactivity (Grace et al., 1984). It has been well documented that burst formation increases the reliability of information transfer. Additionally, bursts and spikes can develop a parallel code, in which they can promote various stimulus features in the same spike train. To elucidate the contribution of H‐current on VTA DA neurons spontaneous firing patterns we perfused H‐current blocker (ZD 7288) through a double barrel pipette and evaluated its effect. H‐current blockade significantly reduced firing rate, bursting frequency and percent of spikes in burst in VTA DA neurons. Neuroadaptations in this network are hypothesized to trigger various neurobiological diseases including drug addiction. Reduction of spontaneous firing patterns through H‐current blockade could serve as a possible modulator of conditions related to VTA DA hyperexcitability.Support or Funding InformationNational Institute of General Medical Sciences (2SC1GM084854) National Center for Research Resources (5R25GM061838‐15, 2G12‐RR003051) National Institute on Minority Health and Health Disparities (8G12‐MD007600) NSF Partnerships in International Research and Education (PIRE) program Neural Mechanisms of Reward & Decision (OISE‐1545803) Research initiative for Scientific Enhancement RISE (5R25GM061151‐18)