Dopamine Neuron Population Research Articles

Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins.

SUMMARYDopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson’s disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6+ population in the ventral SNc includes an Aldh1a1+ subset and is enriched in gene pathways that underpin vulnerability. Sox6+ neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6− neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions.

Nicotine Administration Normalizes Behavioral and Neurophysiological Perturbations in the MAM Rodent Model of Schizophrenia.

BackgroundThe present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia (SCZ) to evaluate the hypothesis that individuals with SCZ smoke in an attempt to “self-medicate” their symptoms through nicotine (NIC) intake.MethodsTo explore this question, we examined the effects of acute and chronic administration of NIC in 2 established behavioral tests known to be disrupted in the MAM model: prepulse inhibition of startle and novel object recognition. Additionally, we assessed the effects of acute and chronic NIC on 2 indices of the pathophysiology of SCZ modeled by MAM, elevated dopamine neuron population activity in the ventral tegmental area and neuronal activity in the ventral hippocampus, using in vivo electrophysiological recordings.ResultsOur findings demonstrated that both acute and chronic administration of NIC significantly improved deficits in prepulse inhibition of startle and novel object recognition among MAM rats and normalized elevated ventral tegmental area and ventral hippocampal neuronal activity in these animals.ConclusionTogether, these findings of NIC-induced improvement of deficits lend support for a “self-medication” hypothesis behind increased cigarette smoking in SCZ and illustrate the potential utility of nicotinic modulation in future pharmacotherapies for certain SCZ symptoms.

Orchestration of Dopamine Neuron Population Activity in the Ventral Tegmental Area by Caffeine: Comparison With Amphetamine.

BackgroundAmong psychostimulants, the dopamine transporter ligands amphetamine and cocaine display the highest addictive potential; the adenosine receptor antagonist caffeine is most widely consumed but less addictive. Psychostimulant actions of amphetamine were correlated with its ability to orchestrate ventral tegmental dopamine neuron activity with contrasting shifts in firing after single vs repeated administration. Whether caffeine might impinge on dopamine neuron activity has remained elusive.MethodsPopulation activity of ventral tegmental area dopamine neurons was determined by single-unit extracellular recordings and set in relation to mouse behavior in locomotion and conditioned place preference experiments, respectively.ResultsA single dose of caffeine reduced population activity as did amphetamine and the selective adenosine A2A antagonist KW-6002, but not the A1 antagonist DPCPX. Repeated administration of KW-6002 or amphetamine led to drug-conditioned place preference and to unaltered or even enhanced population activity. Recurrent injection of caffeine or DPCPX, in contrast, failed to cause conditioned place preference and persistently reduced population activity. Subsequent to repetitive drug administration, re-exposure to amphetamine or KW-6002, but not to caffeine or DPCPX, was able to reduce population activity.ConclusionsBehavioral sensitization to amphetamine is attributed to persistent activation of ventral tegmental area dopamine neurons via the ventral hippocampus. Accordingly, a switch from acute A2A receptor-mediated reduction of dopamine neuron population activity to enduring A1 receptor-mediated suppression is correlated with tolerance rather than sensitization in response to repeated caffeine intake.

Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety

Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on β2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.

Peripubertal mGluR2/3 Agonist Treatment Prevents Hippocampal Dysfunction and Dopamine System Hyperactivity in Adulthood in MAM Model of Schizophrenia.

Pomaglumetad methionil (POM), a group 2 metabotropic glutamate receptor (mGluR2/3) agonist, showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations, including early in disease patients. We used the methyazoxymethanol acetate (MAM) rat model of schizophrenia to determine whether POM may prevent the development of dopamine (DA) system dysfunction in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to control (SAL) rats. MAM and SAL rats were administered either POM (3 mg/kg, i.p.), vehicle (1 ml/kg), or no injection during postnatal day (PD) 31-40. In either late adolescence (PD 47-56) or adulthood (PD 83-96), novel object recognition (NOR) was tested, followed by anesthetized in vivo electrophysiological recordings of VTA DA neuron activity or ventral hippocampal (vHPC) pyramidal neuron activity. MAM rats treated with POM demonstrated increased NOR in adulthood compared to no injection MAM rats, but not compared to vehicle-treated MAM rats. POM-treated MAM rats demonstrated normalized DA neuron population activity and vHPC pyramidal neuron activity compared to vehicle and no injection MAM rats in both late adolescence and adulthood. No significant differences were observed across treatment groups in SAL rats. These results suggest that peripubertal mGluR2/3 agonist administration can prevent the emergence of vHPC pyramidal neuron hyperactivity and increased DA neuron population activity in adult MAM rats.

Spatial and temporal scales of dopamine transmission.

Dopamine is a prototypical neuromodulator that controls circuit function through G protein-coupled receptor signalling. Neuromodulators are volume transmitters, with release followed by diffusion for widespread receptor activation on many target cells. Yet, we are only beginning to understand the specific organization of dopamine transmission in space and time. Although some roles of dopamine are mediated by slow and diffuse signalling, recent studies suggest that certain dopamine functions necessitate spatiotemporal precision. Here, we review the literature describing dopamine signalling in the striatum, including its release mechanisms and receptor organization. We then propose the domain-overlap model, in which release and receptors are arranged relative to one another in micrometre-scale structures. This architecture is different from both point-to-point synaptic transmission and the widespread organization thatis often proposed for neuromodulation. It enables the activation of receptor subsets that are within micrometre-scale domains of release sites during baseline activity and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations. This signalling structure, together with the properties of dopamine release, may explain how switches in firing modes support broad and dynamic roles for dopamine and may lead to distinct pathway modulation.

Output-Specific Adaptation of Habenula-Midbrain Excitatory Synapses During Cocaine Withdrawal.

Projections from the lateral habenula (LHb) control ventral tegmental area (VTA) neuronal populations’ activity and both nuclei shape the pathological behaviors emerging during cocaine withdrawal. However, it is unknown whether cocaine withdrawal modulates LHb neurotransmission onto subsets of VTA neurons that are part of distinct neuronal circuits. Here we show that, in mice, cocaine withdrawal, drives discrete and opposing synaptic adaptations at LHb inputs onto VTA neurons defined by their output synaptic connectivity. LHb axons innervate the medial aspect of VTA, release glutamate and synapse on to dopamine and non-dopamine neuronal populations. VTA neurons receiving LHb inputs project their axons to medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral hypothalamus (LH). While cocaine withdrawal increases glutamate release from LHb onto VTA-mPFC projectors, it reduces presynaptic release onto VTA-NAc projectors, leaving LHb synapses onto VTA-to-LH unaffected. Altogether, cocaine withdrawal promotes distinct adaptations at identified LHb-to-VTA circuits, which provide a framework for understanding the circuit basis of the negative states emerging during abstinence of drug intake.

Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia.

BackgroundThe hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity.MethodsHere we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats).ResultsAberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats.ConclusionTaken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.

Dopamine and relapse to drug seeking.

The actions of dopamine are essential to relapse to drug seeking but we still lack a precise understanding of how dopamine achieves these effects. Here we review recent advances from animal models in understanding how dopamine controls relapse to drug seeking. These advances have been enabled by important developments in understanding the basic neurochemical, molecular, anatomical, physiological and functional properties of the major dopamine pathways in the mammalian brain. The literature shows that although different forms of relapse to seeking different drugs of abuse each depend on dopamine, there are distinct dopamine mechanisms for relapse. Different circuit-level mechanisms, different populations of dopamine neurons and different activity profiles within these dopamine neurons, are important for driving different forms of relapse. This diversity highlights the need to better understand when, where and how dopamine contributes to relapse behaviours.

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

Therapeutic effects of TP5, a Cdk5/p25 inhibitor, in in vitro and in vivo models of Parkinson's disease.

Parkinson’s Disease (PD) is a chronic progressive neurodegenerative disease. Current treatments for PD are symptomatic and only increase striatal dopamine levels. Proactive neuroprotective approaches that slow the progression of PD and maintain appropriate dopamine neuron populations are needed to treat the disease. One suggested mechanism contributing to the pathology of PD involves the binding of cyclin-dependent kinase 5 (Cdk5) to p25, creating a hyperactivated complex to induce cell death. The objective of this study is to investigate the neuroprotective and neurorestorative properties of Truncated Peptide 5 (TP5), a derivative of the p35 activator involved in Cdk5 regulation, via the inhibition of Cdk5/p25 complex function. SH-SY5Y cell line and the nematode Caenorhabditis elegans were exposed to paraquat (PQ), an oxidative stressor, to induce Parkinsonian phenotypes. TP5 was administered prior to PQ exposure to determine its neuroprotective effects and, in further experiments, after PQ exposure to examine its neurorestorative effects. In the SH-SY5Y cell line, TP5 was found to have neuroprotective effects using a cell viability assay and demonstrated neuroprotective and neurorestorative effects in C. elegans by examining dopaminergic neurons and dopamine-dependent behaviour. TP5 decreased elevated Cdk5 activation in worms that were exposed to PQ. TP5’s inhibition of Cdk5/p25 hyperactivity led to the protection of dopamine neurons in these PD models. This suggests that TP5 can act as a potential therapeutic drug towards PD.

Adolescent Exposure to WIN 55212-2 Render the Nigrostriatal Dopaminergic Pathway Activated During Adulthood.

BackgroundDuring adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood.MethodsMale Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72–78).ResultsRepeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure.ConclusionsThese results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.

The mGluR2/3 agonist pomaglumetad methionil normalizes aberrant dopamine neuron activity via action in the ventral hippocampus.

The group 2 metabotropic glutamate receptor (mGluR2/3) agonist, pomaglumetad methionil (POM), showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations. Although previous studies have shown that mGluR2/3 agonists have no effect on dopamine (DA) in wild type rats, we used the methylzoxymethanol acetate (MAM) model to determine whether POM may indirectly normalize DA neuron activity in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to SAL rats, using in vivo, anesthetized, electrophysiological recordings. POM dose-dependently reduced the number of spontaneously active DA neurons in the VTA of MAM rats to control levels without affecting DA firing in SAL rats, which persisted following 14d repeated treatment with POM. In female MAM rats, POM significantly reduced DA neuron population activity only during proestrous and estrous stages. MAM rats also demonstrated dose-dependent improvement in novel object recognition following acute POM, which was not observed in SAL rats. Similar to the MAM rats, DA neuron population activity was increased in a hippocampal-dependent manner following acute restraint stress. Administration of POM prior to 2 h restraint stress prevented the restraint-induced increase in DA neuron population activity, and this effect was blocked by pretreatment with an mGluR2/3 antagonist. Thus, the ability of POM to reduce the hyperdopaminergic activity in both MAM rats and in wild type rats following restraint stress suggests that it can indirectly regulate DA neuron activity, which may underlie its potential therapeutic effects.

Occasion setters determine responses of putative DA neurons to discriminative stimuli

Midbrain dopamine (DA) neurons are involved in the processing of rewards and reward-predicting stimuli, possibly analogous to reinforcement learning reward prediction errors. Here we studied the activity of putative DA neurons (n = 37) recorded in the ventral tegmental area of rats (n = 6) performing a behavioural task involving occasion setting. In this task an occasion setter (OS) indicated that the relationship between a discriminative stimulus (DS) and reinforcement is in effect, so that reinforcement of bar pressing occurred only after the OS (tone or houselight) was followed by the DS (houselight or tone). We found that responses of putative DA cells to the DS were enhanced when preceded by the OS, as were behavioural responses to obtain rewards. Surprisingly though, we did not find a homogeneous increase in the mean activity of the population of putative DA neurons to the OS, contrary to predictions of standard temporal-difference models of DA neurons. Instead, putative DA neurons exhibited a heterogeneous response on a single unit level, so that some units increased and others decreased their activity as a response to the OS. Similarly, putative non-DA cells did not show a homogeneous response to the DS on a population level, but also had heterogeneous responses on a single unit level. The heterogeneity in the responses of neurons in the ventral tegmental area may reflect how DA neurons encode context and point to local differences in DA signalling.

Modulation of Dopamine for Adaptive Learning: A Neurocomputational Model.

There have been many proposals that learning rates in the brain are adaptive, in the sense that they increase or decrease depending on environmental conditions. The majority of these models are abstract and make no attempt to describe the neural circuitry that implements the proposed computations. This article describes a biologically detailed computational model that overcomes this shortcoming. Specifically, we propose a neural circuit that implements adaptive learning rates by modulating the gain on the dopamine response to reward prediction errors, and we model activity within this circuit at the level of spiking neurons. The model generates a dopamine signal that depends on the size of the tonically active dopamine neuron population and the phasic spike rate. The model was tested successfully against results from two single-neuron recording studies and a fast-scan cyclic voltammetry study. We conclude by discussing the general applicability of the model to dopamine mediated tasks that transcend the experimental phenomena it was initially designed to address.

Ventral Tegmental Dopamine Neurons Control the Impulse Vector during Motivated Behavior

The ventral tegmental area (VTA) is a major source of dopamine, especially to the limbic brain regions. Despite decades of research, the function of VTA dopamine neurons remains controversial. Here, using a novel head-fixed behavioral system with five orthogonal force sensors, we show for the first time that the activity of dopamine neurons precisely represents the impulse vector (force exerted over time) generated by the animal. Distinct populations of VTA dopamine neurons contribute to components of the impulse vector in different directions. Optogenetic excitation of these neurons shows a linear relationship between signal injected and impulse generated. Optogenetic inhibition paused force generation or produced force in the backward direction. At the same time, these neurons also regulate the initiation and execution of anticipatory licking. Our results indicate that VTA dopamine controls the magnitude, direction, and duration of force used to move toward or away from any motivationally relevant stimuli.

Spiking and Membrane Properties of Rat Olfactory Bulb Dopamine Neurons.

The mammalian olfactory bulb (OB) has a vast population of dopamine (DA) neurons, whose function is to increase odor discrimination through mostly inhibitory synaptic mechanisms. However, it is not well understood whether there is more than one neuronal type of OB DA neuron, how these neurons respond to different stimuli, and the ionic mechanisms behind those responses. In this study, we used a transgenic rat line (hTH-GFP) to identify fluorescent OB DA neurons for recording via whole-cell electrophysiology. These neurons were grouped based on their localization in the glomerular layer (“Top” vs. “Bottom”) with these largest and smallest neurons grouped by neuronal area (“Large” vs. “Small,” in μm2). We found that some membrane properties could be distinguished based on a neuron’s area, but not by its glomerular localization. All OB DA neurons produced a single action potential when receiving a sufficiently depolarizing stimulus, while some could also spike multiple times when receiving weaker stimuli, an activity that was more likely in Large than Small neurons. This single spiking activity is likely driven by the Na+ current, which showed a sensitivity to inactivation by depolarization and a relatively long time constant for the removal of inactivation. These recordings showed that Small neurons were more sensitive to inactivation of Na+ current at membrane potentials of −70 and −60 mV than Large neurons. The hyperpolarization-activated H-current (identified by voltage sags) was more pronounced in Small than Large DA neurons across hyperpolarized membrane potentials. Lastly, to mimic a more physiological stimulus, these neurons received ramp stimuli of various durations and current amplitudes. When stimulated with weaker/shallow ramps, the neurons needed less current to begin and end firing and they produced more action potentials at a slower frequency. These spiking properties were further analyzed between the four groups of neurons, and these analyses support the difference in spiking induced with current step stimuli. Thus, there may be more than one type of OB DA neuron, and these neurons’ activities may support a possible role of being high-pass filters in the OB by allowing the transmission of stronger odor signals while inhibiting weaker ones.

Differential effects of Δ9-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model.

Social withdrawal in the sub-chronic phencyclidine (PCP) rat model, a behavioral correlate of the negative symptoms of schizophrenia, results from deficits in brain endocannabinoid transmission. As cannabis intake has been shown to affect negatively the course and expression of psychosis, we tested whether the beneficial effects of endocannabinoid-mediated CB1 activation on social withdrawal in PCP-treated rats (5 mg/kg, twice daily for 7 days)also occurred after administration of Δ9-tetrahydrocannabinol (THC; 0.1, 0.3, 1.0 mg/kg, i.p.). In addition, we assessed whether THC affected two correlates of positive symptoms: 1) motor activity induced by d-amphetamine (0.5 mg/kg, i.p.), and 2) dopamine neuron population activity in the ventral tegmental area (VTA). After the motor activity test, the brains from d-amphetamine-treated animals were collected and processed for measurements of endocannabinoids and activation of Akt/GSK3β, two molecular markers involved in the pathophysiology of schizophrenia. In control rats, THC dose-dependently produced social interaction deficits and aberrant VTA dopamine neuron population activity similar to those observed in PCP-treated animals. In PCP-treated rats, only the lowest dose of THC reversed PCP-induced deficits, as well as PCP-induced elevation of the endocannabinoid anandamide (AEA) in the nucleus accumbens. Last, THC activated the Akt/GSK3β pathway dose-dependently in both control and PCP-treated animals. Taken together, these data suggest that only low doses of THC have beneficial effects on behavioral, neurochemical and electrophysiological correlates of schizophrenia symptoms. This observation may shed some light on the controversial hypothesis of marijuana use as self-medication in schizophrenic patients.

DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release.

Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.

The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability.

Unregulated stress during critical periods of development is proposed to drive deficits consistent with schizophrenia in adults. If accurate, reopening the critical period could make the adult susceptible to pathology. We evaluated the impact of early adolescent and adult stress exposure (combination of daily footshock for 10 days and 3 restraint sessions) on 1) midbrain dopamine (DA) neuron activity, 2) ventral hippocampal (vHipp) pyramidal neuron activity, and 3) the number of parvalbumin (PV) interneurons in the vHipp and their associated perineuronal nets (PNNs). Ventral tegmental area (VTA) DA neuron population activity and vHipp activity was increased 1–2 and 5–6 weeks post-adolescent stress, along with a decrease in the number of PV+, PNN+, PV+/PNN+ cells in the vHipp, which are consistent with the MAM model of schizophrenia. In contrast, adult stress decreased VTA DA neuron population activity only at 1–2 weeks post-stress, which is consistent with what has been observed in animal models of depression, without impacting vHipp activity and PV/PNN expression. Administration of valproate (VPA), which can re-instate the critical period of plasticity via histone deacetylase (HDAC) inhibition, caused adult stress to produce changes similar to those induced by adolescent stress, presumably by increasing stress vulnerability to early adolescent levels. Our findings indicate that timing of stress is a critical determinant of the pathology produced in the adult: adolescent stress led to circuit deficits that recapitulates schizophrenia, whereas adult stress induced a depression-like hypodopaminergic state. Reopening the critical period in the adult restores vulnerability to stress-induced pathology resembling schizophrenia.