Dopamine Neuron Firing Research Articles

Nicotine, recognized as the principal addictive component in tobacco, is mechanistically linked to its interaction with neuronal nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels composed of five transmembrane subunits, with the α4β2 receptor subtype being the most common in the brain, playing a crucial role in the behavioral effects of nicotine. When nicotine binds to α4β2 nAChR, it significantly enhances the firing rate and burst firing of dopamine neurons in the brain, thereby activating the mesolimbic dopamine system. This system promotes the formation of nicotine addiction in the early stages of addiction through rewarding sensory stimulation and associative learning. The α4β2 nAChR subunit has been identified as the principal subtype implicated in the pathogenesis of nicotine addiction. However, other nAChRs subtypes also play important roles in the onset and maintenance of nicotine addiction. Understanding the relationship between nicotine addiction and nAChR subtypes is crucial for fully uncovering the neurobiological mechanism behind its addictive properties and lays the foundation for developing more targeted smoking cessation strategies.

Differential effects of psilocybin and lisuride on serotonin and dopamine neuronal activity and behavior.

Adolescent isolation disrupts medial amygdala and ventral tegmental area maturation and sex-specifically dysregulates transcriptional responses to cocaine and stress.

INTRODUCTION:Ventral tegmental area (VTA) dopamine has been implicated in neuropsychiatric symptoms observed in Alzheimer’s disease (AD) patients. Dopaminergic dysfunction and aberrant firing are observed in mouse AD models, but the specific roles of Aβ and tau have not been determined.METHODS:We performed electrophysiological recordings of single VTA dopamine neuron firing in the 3xTg-AD model, followed by recordings in amyloid (APPNL-G-F)- and human tau (hTau)-based models to determine the pathological triggers of impaired firing.RESULTS:In vivo dopamine neuron recordings showed fewer spikes in defined bursts in 3xTg-AD mice versus controls. Ex vivo studies showed an impaired ability to sustain firing during depolarization, which was mimicked with depolarized current in wild type neurons. Dopamine neurons transduced with hTau reflected firing aberrations and impaired bursting, but the effects were not recapitulated in the APPNL-G-F model,DISCUSSION:These results suggest that hTau specifically induces hyperexcitable states within individual dopamine neurons, disrupting burst firing. This dopaminergic dysfunction could compromise reward learning and contribute to the psychiatric symptoms observed in AD.

Glycine-gated extrasynaptic NMDARs activated during glutamate spillover drive burst firing in nigral dopamine neurons.

Multiple brain regions need to coordinate activity to support cognitive flexibility and behavioral adaptation. Neural activity in both the hippocampus (HPC) and medial prefrontal cortex (mPFC) is known to represent the spatial context and is sensitive to reward and rule alterations. Midbrain dopamine (DA) activity is key to reward-seeking behavior and learning. There is abundant evidence that midbrain DA modulates HPC and PFC activity. However, it remains underexplored how these networks engage dynamically and coordinate temporally when animals adjust their behavior according to changing reward contingencies. In particular, is there any relationship between DA reward prediction change during rule switching and rule representation changes in mPFC and CA1? We addressed these questions using simultaneous recordings of neuronal population activity from the hippocampal area CA1, mPFC, and ventral tegmental area (VTA) in male TH-Cre rats performing two spatial working memory tasks with frequent rule switches in blocks of trials. CA1 and mPFC ensembles showed rule-specific activity both during maze running and at reward locations, with mPFC rule coding more consistent across animals compared with CA1. Optogenetically tagged VTA DA neuron firing activity responded to and predicted reward outcome. We found that the correct prediction in DA emerged gradually over trials after rule switching in coordination with transitions in mPFC and CA1 ensemble representations of the current rule after a rule switch, followed by behavioral adaptation to the correct rule sequence. Therefore, our study demonstrates a crucial temporal coordination between the rule representation in mPFC/CA1, the dopamine reward signal, and behavioral strategy.

Cognitive impairment is a common and challenging side effect of cranial radiation therapy for brain tumors, though its precise mechanisms remain unclear. The mesocortical dopaminergic pathway, known to play a key role in cognitive function, is implicated in several neuropsychiatric disorders, yet its involvement in radiation-induced cognitive dysfunction is unexplored. Here, with using in vivo multi-electrode array recordings of both anesthetized and free-moving rats to monitor the firing activities of dopamine neurons in the ventral tegmental area (VTA) and local field potentials in both the prefrontal cortex (PFC) and VTA, as well as the immunofluorescence assays and western blotting, we report that cranial irradiation transiently altered VTA dopamine neuron firing patterns without affecting overall firing rates and led to sustained reductions in both “awake” and total dopamine neuron density. Additionally, radiation exposure impaired D2 receptor function and disrupted connectivity between the PFC and VTA. These multifaceted disruptions in the mesocortical dopamine signaling may underlie the development of radiation-induced cognitive dysfunction. These findings pave the way for novel research to prevent or reverse radiation-induced injury, ultimately improving the quality of life for brain tumor survivors.

Multiple brain regions need to coordinate activity to support cognitive flexibility and behavioral adaptation. Neural activity in both the hippocampus (HPC) and prefrontal cortex (PFC) is known to represent spatial context and is sensitive to reward and rule alterations. Midbrain dopamine (DA) activity is key in reward seeking behavior and learning. There is abundant evidence that midbrain DA modulates HPC and PFC activity. However, it remains underexplored how these networks engage dynamically and coordinate temporally when animals must adjust their behavior according to changing reward contingencies. In particular, is there any relationship between DA reward prediction change during rule switching, and rule representation changes in PFC and CA1? We addressed these questions using simultaneous recording of neuronal population activity from the hippocampal area CA1, PFC and ventral tegmental area (VTA) in male TH-Cre rats performing two spatial working memory tasks with frequent rule switches in blocks of trials. CA1 and PFC ensembles showed rule-specific activity both during maze running and at reward locations, with PFC rule coding more consistent across animals compared to CA1. Optogenetically tagged VTA DA neuron firing activity responded to and predicted reward outcome. We found that the correct prediction in DA emerged gradually over trials after rule-switching in coordination with transitions in PFC and CA1 ensemble representations of the current rule after a rule switch, followed by behavioral adaptation to the correct rule sequence. Therefore, our study demonstrates a crucial temporal coordination between the rule representation in PFC/CA1, the dopamine reward signal and behavioral strategy.

Transient changes in the firing of midbrain dopamine neurons have been closely tied to the unidimensional value-based prediction error contained in temporal difference reinforcement learning models. However, whereas an abundance of work has now shown how well dopamine responses conform to the predictions of this hypothesis, far fewer studies have challenged its implicit assumption that dopamine is not involved in learning value-neutral features of reward. Here, we review studies in rats and humans that put this assumption to the test, and which suggest that dopamine transients provide a much richer signal that incorporates information that goes beyond integrated value.

Major Depressive Disorder (MDD) is a devastating, multifactorial disease with limited pharmacological treatment options. Patients with MDD exhibit alterations in their dopamine (DA) signaling pathways through the midbrain ventral tegmental area (VTA). A similar observation is also detected in preclinical models of stress - mice exhibit behavioral and physiological impairments following chronic social defeat stress (CSDS). Prior studies demonstrate that CSDS-susceptible mice have increased VTA DA neuronal excitability, in part driven by an upregulation in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Inhibiting HCN channels with known inhibitors such as Cilobradine alleviates the negative behavioral effects of CSDS. Here, we aimed to identify Cilobradine analogs with improved neural tropism and inhibitory efficacy. Two compounds, MS7710 and MS7712, differing by their left-hand side moieties, have a similar, potent inhibitory effect on VTA DA Ih currents as compared to Cilobradine, and a greater inhibitory effect than Cilobradine on VTA DA firing rate. We demonstrate that MS7710 and MS7712 have superior brain/plasma concentration ratios as compared to Cilobradine. They were efficacious at inhibiting VTA DA neuron firing rate and bursting activity in CSDS-susceptible male mice at lower doses than Cilobradine, which was recapitulated in female CSDS-susceptible mice with MS7710. Finally, we define that a single intraperitoneal injection of MS7710 ameliorates CSDS-induced social interaction deficits and reward-associated cognitive inflexibility for at least two weeks in male and female mice. These findings yield a novel HCN channel inhibitor with improved neural tropism and stress-alleviating effects that could provide a basis for future antidepressant drug discovery.

Abstract BackgroundThe circadian rhythm controls physiological functions across by responding to environmental light cues. fluctuations in this rhythm, such as those induced by irregular work schedules, have been associated with adverse health outcomes, this study aims to assess the increased likelihood risk of developing Alzheimer’s dementia for workers with irregular work schedules.MethodsExploring and referencing studies on Alzheimer disease (AD) which had proved an undeniable relationship between dopamine levels with AD onset, this study showcases the relationship of dopamine levels and circadian rhythm and its effect indirectly on Alzheimer as a predisposing factor of AD.Discussion and ResultTraditionally thought to be the result of neurodegenerative processes, disturbances of the circadian rhythm and sleep‐wake cycle are common symptoms seen in people with AD. However, there may be a possible reciprocal association between circadian abnormalities and the development of AD, suggesting that they may also be risk factors. Circadian rhythms significantly influence dopamine levels throughout the day. This is demonstrated by in vivo studies that show heightened dopamine neuronal firing during the day (7:00‐11:00 h) and at the start of the night (19:00‐23:00 h), with significantly fewer spikes firing in between (11:00‐15:00 h). Furthermore The dopaminergic system has been implicated in the pathogenesis of Alzheimer’s disease and its progression, with patients who suffer from Alzheimer showing low dopamine levels.ConclusionConsidering the influence of circadian rhythm on dopamine levels, there seems to be a potential interplay between circadian disruptions and neurological health, warranting further investigation into the relationship between circadian rhythm disturbances and the risk of Alzheimer’s dementia onset.

Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies.

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb-RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ9-tetrahydrocannabinol (THC) dependence, adult male Sprague-Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5-7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo-mesencephalic circuit are implicated in the mechanisms underlying substance use disorders.

The orbitofrontal cortex (OFC) and hippocampus (HC) both contribute to the cognitive maps that support flexible behavior. Previously, we used the dopamine neurons to measure the functional role of OFC. We recorded midbrain dopamine neurons as rats performed an odor-based choice task, in which expected rewards were manipulated across blocks. We found that ipsilateral OFC lesions degraded dopaminergic prediction errors, consistent with reduced resolution of the task states. Here we have repeated this experiment in male rats with ipsilateral HC lesions. The results show HC also shapes the task states, however unlike OFC, which provides information local to the trial, the HC is necessary for estimating upper-level hidden states that distinguish blocks. The results contrast the roles of the OFC and HC in cognitive mapping and suggest that the dopamine neurons access rich information from distributed regions regarding the environment’s structure, potentially enabling this teaching signal to support complex behaviors.

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Role of ventral tegmental area dopamine neurons in fear memory retention in post-traumatic stress disorder model rats

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.

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus and ventral pallidum afferents. We next determined the phase resetting curve, the reversal potential for GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs), and the average interspike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the interspike interval or phase. Simulations were performed to predict the pause duration resulting from the synchronous arrival of multiple uIPSGs and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns, including pauses that have been implicated in reinforcement.

Cannabis consumption has increased from 1.5% to 2.5% in Canada between 2012 and 2019. Clinical studies have indicated effects of prenatal cannabis exposure on birth weight, substance use, and neurodevelopmental disorders, but are confounded by several difficult to control variables. Animal models allow for examination of the mechanism of cannabis-induced changes in neurodevelopment and behavior, while controlling dose and timing. Several animal models of prenatal cannabis exposure exist which provide varying levels of construct validity, control of dose, and exposure to maternal stress. Using a voluntary oral consumption model, mouse dams received 5 mg/kg Δ9-tetrahydrocannabinol (THC) whole cannabis oil in peanut butter daily from gestational day 1 (GD1) to postnatal day 10 (PD10). At GD1, GD18, PD1, PD10, and PD15, maternal plasma was collected; pup brains were collected from GD18 onward. Pup brains had higher levels of THC and cannabidiol at each time point, each of which persisted in maternal plasma and pup brains past the end of treatment (PD15). Male and female adolescent offspring were examined for changes to ventral tegmental area (VTA) dopamine neuron activity and cocaine-seeking behavior. Prenatal and early postnatal (GD1-PD10) cannabis-exposed male, but not female mice had decreased gamma-aminobutyric acid (GABAergic) input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons. Cannabis-exposed offspring showed faster decay of N-methyl-D-aspartate (NMDA) currents in both sexes. However, no differences in cocaine-seeking behavior were noted. These data characterize a voluntary prenatal cannabis exposure model and demonstrates VTA dopamine neuronal activity is disinhibited in offspring.

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.