Firing Of Midbrain Dopamine Neurons Research Articles

Adaptor protein-3 produces synaptic vesicles that release phasic dopamine

The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.

Striatal Dopamine Signals and Reward Learning.

We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of sensory inputs and actions lead to successful outcomes in specific circumstances. Neuronal circuits of the basal ganglia have been strongly implicated in action selection, as well as the learning and execution of goal-directed behaviors, with accumulating evidence supporting the hypothesis that midbrain dopamine neurons might encode a reward signal useful for learning. Here, we review evidence suggesting that midbrain dopaminergic neurons signal reward prediction error, driving synaptic plasticity in the striatum underlying learning. We focus on phasic increases in action potential firing of midbrain dopamine neurons in response to unexpected rewards. These dopamine neurons prominently innervate the dorsal and ventral striatum. In the striatum, the released dopamine binds to dopamine receptors, where it regulates the plasticity of glutamatergic synapses. The increase of striatal dopamine accompanying an unexpected reward activates dopamine type 1 receptors (D1Rs) initiating a signaling cascade that promotes long-term potentiation of recently active glutamatergic input onto striatonigral neurons. Sensorimotor-evoked glutamatergic input, which is active immediately before reward delivery will thus be strengthened onto neurons in the striatum expressing D1Rs. In turn, these neurons cause disinhibition of brainstem motor centers and disinhibition of the motor thalamus, thus promoting motor output to reinforce rewarded stimulus-action outcomes. Although many details of the hypothesis need further investigation, altogether, it seems likely that dopamine signals in the striatum might underlie important aspects of goal-directed reward-based learning.

GRK3 deficiency elicits brain immune activation and psychosis

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3−/− mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3−/− mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.

Brief, But Not Prolonged, Pauses in the Firing of Midbrain Dopamine Neurons Are Sufficient to Produce a Conditioned Inhibitor.

Prediction errors are critical for associative learning. In the brain, these errors are thought to be signaled, in part, by midbrain dopamine neurons. However, although there is substantial direct evidence that brief increases in the firing of these neurons can mimic positive prediction errors, there is less evidence that brief pauses mimic negative errors. Whereas pauses in the firing of midbrain dopamine neurons can substitute for missing negative prediction errors to drive extinction, it has been suggested that this effect might be attributable to changes in salience rather than the operation of this signal as a negative prediction error. Here we address this concern by showing that the same pattern of inhibition will create a cue able to meet the classic definition of a conditioned inhibitor by showing suppression of responding in a summation test and slower learning in a retardation test. Importantly, these classic criteria were designed to rule out explanations founded on attention or salience; thus the results cannot be explained in this manner. We also show that this pattern of behavior is not produced by a single, prolonged, ramped period of inhibition, suggesting that it is precisely timed, sudden change and not duration that conveys the teaching signal.SIGNIFICANCE STATEMENT Here we show that brief pauses in the firing of midbrain dopamine neurons are sufficient to produce a cue that meets the classic criteria defining a conditioned inhibitor, or a cue that predicts the omission of a reward. These criteria were developed to distinguish actual learning from salience or attentional effects; thus these results formally show that brief pauses in the firing of dopamine neurons can serve as key teaching signals in the brain. Interestingly, this was not true for gradual prolonged pauses, suggesting it is the dynamic change in firing that serves as the teaching signal.

Social interactions impact on the dopaminergic system and drive individuality

Individuality is a striking feature of animal behavior. Individual animals differ in traits and preferences which shape their interactions and their prospects for survival. However, the mechanisms underlying behavioral individuation are poorly understood and are generally considered to be genetic-based. Here, we devised a large environment, Souris City, in which mice live continuously in large groups. We observed the emergence of individual differences in social behavior, activity levels, and cognitive traits, even though the animals had low genetic diversity (inbred C57BL/6J strain). We further show that the phenotypic divergence in individual behaviors was mirrored by developing differences in midbrain dopamine neuron firing properties. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animal’s traits and its dopamine firing pattern. Individuality can rapidly change upon social challenges, and does not just depend on the genetic status or the accumulation of small differences throughout development.

P.3.c.010 - Modulation of sub-chronic ketamine-induced locomotor sensitisation by midbrain dopamine neuron firing

P.3.c.010 - Modulation of sub-chronic ketamine-induced locomotor sensitisation by midbrain dopamine neuron firing

Normal Aging Alters Learning and Attention-Related Teaching Signals in Basolateral Amygdala

Normal aging has been associated with an increased propensity to wait for rewards. When this is tested experimentally, rewards are typically offered at increasing delays. In this setting, persistent responding for delayed rewards in aged rats could reflect either changes in the evaluation of delayed rewards or diminished learning, perhaps due to the loss of subcortical teaching signals induced by changes in reward; the loss or diminution of such teaching signals would result in slower learning with progressive delay of reward, which would appear as persistent responding. Such teaching signals have commonly been reported in phasic firing of midbrain dopamine neurons; however, similar signals have also been found in reward-responsive neurons in the basolateral amygdala (ABL). Unlike dopaminergic teaching signals, those in ABL seem to reflect surprise, increasing when reward is either better or worse than expected. Accordingly, activity is correlated with attentional responses and with the speed of learning after surprising increases or decreases in reward. Here we examined whether these attention-related teaching signals might be altered in normal aging. Young (3-6 months) and aged (22-26 months) male Long-Evans rats were trained on a discounting task used previously to demonstrate these signals. As expected, aged rats were less sensitive to delays, and this change was associated with a loss of attentional changes in orienting behavior and neural activity. These results indicate that normal aging alters teaching signals in the ABL. Changes in these teaching signals may contribute to a host of age-related cognitive changes.

Augmentation by escitalopram, but not citalopram or R‐citalopram, of the effects of low‐dose risperidone: Behavioral, biochemical, and electrophysiological evidence

Antidepressant drugs are frequently used to treat affective symptoms in schizophrenia. We have recently shown that escitalopram, but not citalopram or R-citalopram, increases firing rate and burst firing of midbrain dopamine neurons, potentiates cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission and enhances cognition, effects that might influence the outcome of concomitant antipsychotic medication. Here, we studied, in rats, the behavioral and neurobiological effects of adding escitalopram, citalopram, or R-citalopram to the second-generation antipsychotic drug risperidone. We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect (EPS) liability using a catalepsy test, dopamine outflow in the medial prefrontal cortex (mPFC) and nucleus accumbens using in vivo microdialysis in freely moving animals, and NMDA receptor-mediated transmission in the mPFC using intracellular electrophysiological recording in vitro. Only escitalopram (5 mg/kg), but not citalopram (10 mg/kg), or R-citalopram (10 mg/kg), dramatically enhanced the antipsychotic-like effect of a low dose of risperidone (0.25 mg/kg), without increasing catalepsy. Given alone, escitalopram, but not citalopram or R-citalopram, markedly enhanced both cortical dopamine output and NMDA receptor-mediated transmission. Addition of escitalopram and to some extent R-citalopram, but not citalopram, significantly enhanced both cortical dopamine output and cortical NMDA receptor-mediated transmission induced by a suboptimal dose/concentration of risperidone. These results suggest that adjunct treatment with escitalopram, but not citalopram, may enhance the effect of a subtherapeutic dose of risperidone on positive, negative, cognitive, and depressive symptoms in schizophrenia, yet without increased EPS liability.

The Face of Uncertainty Eats

The idea that foods rich in fat and sugar may be addictive has generated much interest, as well as controversy, among both scientific and lay communities. Recent research indicates that fatty and sugary food in-and-of itself is not addictive. Rather, the food and the context in which it is consumed interact to produce an addiction-like state. One of the contexts that appears to be important is the intermittent opportunity to consume foods rich in fat and sugar in environments where food is plentiful. Animal research indicates that, under these conditions, intake of the fatty sugary food escalates across time and binge-type behavior develops. However, the mechanisms that account for the powerful effect of intermittency on ingestive behavior have only begun to be elucidated. In this review, it is proposed that intermittency stimulates appetitive behavior that is associated with uncertainty regarding what, when, and how much of the highly palatable food to consume. Uncertainty may stimulate consumption of optional fatty and sugary treats due to differential firing of midbrain dopamine neurons, activation of the stress axis, and involvement of orexin signaling. In short, uncertainty may produce an aversive state that bingeing on palatable food can alleviate, however temporarily. "Food addiction" may not be "addiction" to food at all; it may be a response to uncertainty within environments of food abundance.

Dopaminergic cells repolarization induced by calcium and Na+/K+ ATPase pumps

The firing pattern in dopaminergic (DA) neurons influences the extracellular concentration of dopamine in projection areas. A burst produces a greater phasic increase in dopamine concentration than a tonic one [1]. Burst firing of midbrain dopamine neurons is associated with behavioral motivation and reward mechanisms. At the same time, dopamine pathway, which is one of the oldest responsible for biological survival and present even in worms and flies, is profoundly altered by cocaine. In particular, limbic system, which controls emotional responses and links them with memories, has it most cocaine-sensitive site located in nucleus accumbens. Parkinson’s disease (PD) is one of the most common diseases among the aging and affects approximately 1% of the population worldwide [2]. There is no known cure for PD, and with an ageing population as the average life span increases due to a general improvement in health care, understanding the cause and progression of the neurodegenerative process is as challenging as it is necessary. In PD, neurons of the substantia nigra pars compacta progressively degenerate and when about 50% of them are lost the amount of dopamine available for neurotransmission in the corpus striatum is lowered by 80% the external signs of the disease are apparent. PD is not simply due to dopamine deficit, but is rather a multisystem disorder. For example, norepinephrine may play a key role in compensating for DA neurons lose in the early stages of the disease [3]. Therefore, understanding the mechanism of tonic and burst firing in DA neurons may lead to a better understanding and possible solutions for a series of neurodegenerative diseases.

Pharmacological Manipulation of Kynurenic Acid

The kynurenine pathway constitutes the main route of tryptophan degradation and generates the production of several neuroactive compounds; quinolinic acid is an excitotoxic NMDA receptor agonist, 3-hydroxykynurenine is a free-radical generator and kynurenic acid (KYNA) is an antagonist at glutamate and nicotinic receptors. In low micromolar concentrations, KYNA blocks the glycine site of the NMDA receptor and the nicotinic alpha(7) acetylcholine receptor. Knowledge regarding kynurenine metabolites and their involvement in neurophysiological processes has increased dramatically in recent years. In particular, endogenous KYNA appears to tightly control firing of midbrain dopamine neurons and to be involved in cognitive functions. Thus, decreased endogenous levels of rat brain KYNA have been found to reduce firing of these neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brain KYNA levels concomitant with an increased performance in cognitive tests. It is also suggested that kynurenines participate in the pathophysiology of psychiatric disorders. Thus, elevated levels of KYNA have been found in the CSF as well as in the post-mortem brain of patients with schizophrenia. Advantages in understanding how kynurenines can be pharmacologically manipulated may provide new possibilities in the treatment of psychiatric disorders, such as schizophrenia.

Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons

Acute elevation of the endogenous NMDA-receptor antagonist kynurenic acid (KYNA) is associated with an increased neuronal activity of rat ventral tegmental area (VTA) dopamine (DA) neurons and disruption in prepulse inhibition (PPI). In the present study, the effects of subchronic exposure to kynurenine and probenecid (20 mg/kg/day and 10 mg/kg/day, respectively for 14 days), aiming at increasing brain KYNA turnover, on rat VTA dopaminergic firing and on PPI were investigated. This treatment increased neuronal firing of VTA DA neurons, changed the response of these neurons to systemically administered nicotine (3-400 microg/kg, i.v.) and tended to disrupt PPI. Present results show that the effect on firing of VTA DA neurons by acutely elevated levels of brain KYNA also persists following subchronic exposure. In addition, no adaptive changes seem to occur with regard to the electrophysiological effects of KYNA on VTA DA neurons following subchronic treatment with kynurenine and probenecid.