Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration ...of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation of the boundaries of dopaminergic volume transmission. Bursts primarily increase occupancy of D(1) receptors, whereas pauses translate into low occupancy of D(1) and D(2) receptors. Phasic firing patterns, composed of bursts and pauses, reduce the average D(2) receptor occupancy and increase average D(1) receptor occupancy compared with equivalent tonic firing. Receptor occupancy is crucially dependent on synchrony and the balance between tonic and phasic firing modes. Our results provide quantitative insight in the dynamics of volume transmission and complement experimental data obtained with electrophysiology, positron emission tomography, microdialysis, amperometry, and voltammetry.
Progressive loss of nigrostriatal dopamine (DA) neurons is the neuropathological hallmark of Parkinson's disease (PD). Symptoms of the disease can often be treated by DA D2 agonists and thus seem ...related to disinhibition of the indirect striatal pathway. However, there is no evidence that symptoms arise by low extracellular DA concentration or are associated with reduced D2 receptor binding. Here I provide a theoretical analysis of the pathophysiology and postsynaptic adaptation resulting from striatal DA denervation. I found that progressive denervation may alter DA signaling by three independent mechanisms depending on degree of denervation and macroscopic morphology of the lesion. As long as the remaining innervation stays anatomically coherent, denervation reduces phasic variations in extracellular DA, but the DA tone is not changed. The reduction of phasic signaling can be partially compensated by upregulating postsynaptic signaling cascades. However, changes in DA dynamics evade compensation. With 80-99% denervation, a persistent aberrant signal develops in D2-regulated pathways caused by random fluctuations in tonic DA release. Permanent low DA levels occur in regions completely void of innervation. Simulation of l-dopa therapy reduced the aberrant D2 signal. With a high degree of denervation, l-dopa enhanced another aberrant signal, this time in the D1 pathway. This analysis provides a quantitative, physiologically consistent view of the early and late stages of PD, the effect of main therapeutic medications, and potential side effects. The mechanisms described here may also provide an explanation to currently inexplicable pathological phenomena such as psycho stimulant-induced contraversive rotations in animal models.
Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson’s disease. Understanding the basis of such motor ...control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson’s disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate howdysregulation of their firing in early Parkinsonism can impair their effector circuits.
Movement disorders arise from the complex interplay of multiple changes to neural circuits. Successful treatments for these disorders could interact with these complex changes in myriad ways, and as ...a consequence their mechanisms of action and their amelioration of symptoms are incompletely understood. Using Parkinson's disease as a case study, we review here how computational models are a crucial tool for taming this complexity, across causative mechanisms, consequent neural dynamics and treatments. For mechanisms, we review models that capture the effects of losing dopamine on basal ganglia function; for dynamics, we discuss models that have transformed our understanding of how beta-band (15-30 Hz) oscillations arise in the parkinsonian basal ganglia. For treatments, we touch on the breadth of computational modelling work trying to understand the therapeutic actions of deep brain stimulation. Collectively, models from across all levels of description are providing a compelling account of the causes, symptoms and treatments for Parkinson's disease.
Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are ...heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real-time DA signal requires simultaneous knowledge of the synchronized activity of DA cell subpopulations and assessment of the down-stream functional effect of DA release. Because this is not yet possible solely by experimentation in vivo, we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevant DA signal in DA neuron subpopulations projecting to the NAc core and shell in freely moving rats. The approach provides a novel perspective on real-time DA neuron firing and concurrent activation of presynaptic autoreceptors and postsynaptic targets. We first show that individual differences in DA release arise from differences in autoreceptor feedback. The model predicts that extracellular DA concentrations in NAc core result from constant baseline DA firing, whereas DA concentrations in NAc shell reflect highly dynamic firing patters, including synchronized burst firing and pauses. Our models also predict that this anatomical difference in DA signaling is exaggerated by intravenous infusion of cocaine.
Orchestrated signaling from mesolimbic dopamine (DA) neurons is important for initiating appropriate behavior in response to salient stimuli. Thus, subpopulations of mesolimbic DA neurons show different in vitro properties and synaptic inputs depending on their specific projections to the core and shell subterritories of the nucleus accumbens (NAc). However, the functional consequence of these differences is unknown. Here we analyze and model DA dynamics in different areas of the NAc to establish the real-time DA signal. In freely behaving animals, we find that the DA signal from mesencephalic neurons projecting to the NAc shell is dominated by synchronized bursts and pauses, whereas signaling is uniform for core-projecting neurons; this difference is amplified by cocaine.
The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across ...different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multiregion fiber photometry and machine learning-based analysis to decode dopamine dynamics across the striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running, and grooming on a subsecond-to-minute time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action.
Som svar på Karsten Friis’ kritik af Fokkusspalten, ”Når krig blir hverdag”, formulerer denne replik en kort begrebslig, empirisk og normativ afklaring af spaltens anvendelse af begrebet ...militæraktivisme. Begrebsligt påpeger replikken, at militæraktivisme allerede er hyppigt anvendt i litteraturen om skandinaviske landes øgede engagement i internationale militære operationer efter Den Kolde Krig. Empirisk set, er det korrekt, at udviklingen ikke har været lineær, og man kan argumentere for, at Danmark og Norges militæraktivisme var (endnu) større, da Afghanistankrigen var på sit højeste. Dog er begge lande fortsat engageret særligt i NATO-regi, og det er væsentligt at bemærke, at de direkte kampe på landjorden i internationale militære operationer i stigende grad udliciteres til mindre privilegerede lokale og internationale kombattanter. Replikken påpeger, at Friis’ påstand om, at militæraktivisme som begreb udgør en slet skjult kritik af Danmark og Norges militære engagement, beror på en misforståelse. Tværtimod stammer aktivisme fra den danske udenrigspolitiske debat, hvor begrebet anvendes politisk med en række positive konnotationer forbundet med at være aktiv (Pedersen & Ringsmose, 2017). I lyset af afpolitiseringen af Danmarks og Norges krigsdeltagelse velkommer vi fremadrettet yderligere forskningsmæssig og politisk diskussion af militæraktivismen.
Abstract in EnglishReply: Military Activism RevisitedIn response to Karsten Friis’ critique of the special issue When War Becomes Daily Life, this reply outlines a brief conceptual, empirical and normative clarification of the special issue’s use of the concept, military activism. Conceptually, the reply points out that military activism is already a frequently used concept in the academic literature on Scandinavian countries increased engagement in international military operations after the Cold War. Empirically, it is correct that this development has not been linear, and arguably, Denmark and Norway’s military activism was (even more) pronounced, when the war in Afghanistan was at its zenith. However, both countries continue to be engaged particularly in NATO, and significantly, direct battles on the ground are increasingly outsourced to local actors to less privileged local and international combatants. The reply points out, that Friis’s claim that military activism is a concealed critique of Denmark and Norway’s military engagement, is based on a misunderstanding. On the contrary, activism as a concept derives from the Danish foreign policy debate, where the term is used to connote a series of positive attributes associated with being active (Pedersen & Ringsmose, 2017). Considering the depoliticisation of Denmark and Norway’s military activism we welcome further academic and policy discussions about this important issue.
Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimer's Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been ...reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.
•Cortical visual processing is impaired at single cell level in young rTg4510 mice•This is reflected by reduced firing and aberrant synchronicity of pyramidal neurons•Circuit responsivity to GABAergic modulation was compromised in young rTg4510 mice•rTg4510 animals show aberrant cortical theta oscillations prior to neurodegeneration•Abnormal tau phosphorylation enhances susceptibility to epileptogenesis
Midbrain dopamine seems to play an outsized role in motivated behavior and learning. Widely associated with mediating reward-related behavior, decision making, and learning, dopamine continues to ...generate controversies in the field. While many studies and theories focus on what dopamine cells encode, the question of how the midbrain derives the information it encodes is poorly understood and comparatively less addressed. Recent anatomical studies suggest greater diversity and complexity of afferent inputs than previously appreciated, requiring rethinking of prior models. Here, we elaborate a hypothesis that construes midbrain dopamine as implementing a Bayesian selector in which individual dopamine cells sample afferent activity across distributed brain substrates, comprising evidence to be evaluated on the extent to which stimuli in the on-going sensorimotor stream organizes distributed, parallel processing, reflecting implicit value. To effectively generate a temporally resolved phasic signal, a population of dopamine cells must exhibit synchronous activity. We argue that synchronous activity across a population of dopamine cells signals consensus across distributed afferent substrates, invigorating responding to recognized opportunities and facilitating further learning. In framing our hypothesis, we shift from the question of how value is computed to the broader question of how the brain achieves coordination across distributed, parallel processing. We posit the midbrain is part of an "axis of agency" in which the prefrontal cortex (PFC), basal ganglia (BGS), and midbrain form an axis mediating control, coordination, and consensus, respectively.
Dette er introduksjonsartikkelen til fokusnummeret "Når krig blir hverdag. Militæraktivisme i de skandinaviske landenes utenriks- og sikkerhetspolitikk".
Abstract in English: When War Becomes Daily ...LifeThis is the introductory article for the special issue "When War Becomes Daily Life. Military activism in the Scandinavian Countries Foreign and Security Policies".
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