Biology subjects

Ejdrup, A. L.

Publications and source records attributed to Ejdrup, A. L..

5 recordsLinked to original sources

bioRxiv2024

Modelling determinants of region-specific dopamine dynamics in the striatum

Striatal dopamine (DA) release regulates reward-related learning and motivation and is believed to consist of a short-lived phasic and continuous tonic component. Here, we build a large-scale three-dimensional model of extracellular DA dynamics in dorsal (DS) and ventral striatum (VS). The model predicts rapid dynamics in DS with little-to-no basal DA, and slower dynamics in the VS enabling build-up of tonic DA levels. These regional differences do not reflect release-related phenomena but rather differential dopamine transporter (DAT) activity. Interestingly, our simulations posit DAT nanoclustering as a possible regulator of this activity. Receptor binding simulations show that D1 receptor occupancy follows extracellular DA concentration with milliseconds delay, while D2 receptors do not respond to brief pauses in firing but rather integrate DA signal over seconds. Summarized, our model distills recent experimental observations into a computational framework that challenge prevailing paradigms of striatal DA signalling.

neuroscience↗

bioRxiv2022

Behavioral encoding across timescales by region-specificdopamine dynamics

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 multi-region fiber photometry and machine learning-based analysis to decode dopamine dynamics across 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-minutes 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. Significance StatementNew genetically encoded dopamine sensors offer unprecedented temporal resolution for measurement of dopamine release dynamics across different brain regions over extended periods. In this study, we use the dopamine sensor dLight1.3b to decipher the role of dopamine release dynamics in the dorsal (DS) and ventral striatum (VS) of mice during simple, self-paced exploratory behavior. By AI-based splitting of behavioral kinematics into individual motifs, we link differential but highly cooperative dopamine release dynamics of DS and VS with movements on a subsecond-to-minutes time scales. In addition to coupling region-specific dopamine dynamics to behavioral sequences, our study demonstrates the strength of a machine learning-based data analysis pipeline that can be readily applied to other neurotransmitters for which genetically encoded biosensors are available.

neuroscience↗

bioRxiv2022

Within-animal comparison of microdialysis and fiber photometry in amphetamine-exposed mice

A fundamental concept in neuroscience is the transmission of information between neurons via neurotransmitters, -modulators, and - peptides. For the past decades the gold standard for measuring neurochemicals in awake animals has been microdialysis (MD). The emergence of genetically encoded fluorescence-based biosensors, as well as in vivo optical techniques such as fiber photometry (FP), have introduced technologically distinct means of measuring neurotransmission. To directly compare MD and FP, we performed concurrent within-animal recordings of extracellular dopamine (DA) in the dorsal striatum (DS) before and after administration of amphetamine in awake, freely behaving mice expressing the dopamine sensor dLight1.3b. We show that despite temporal differences, MD- and FP-based readouts of DA correlate well within mice. Down-sampling of FP data showed temporal correlation to MD data, with less variance observed using FP. We also present evidence that DA fluctuations periodically reach low levels and naive animals have rapid, pre-drug DA dynamics measured with FP that correlate to the subsequent pharmacodynamics of amphetamine as measured with MD and FP.

neuroscience↗

bioRxiv2022

Relative enrichment - a density-based colocalization measure for single-molecule localization microscopy

Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by current analysis tools that often reduce colocalization to a single value. Here, we describe a new tool specifically designed for determination of co-localization in both 2D and 3D from SMLM data. The approach uses a novel function that describes the relative enrichment of one molecular species on the density distribution of a reference species. The function reframes the question of colocalization by providing a density-context relevant to multiple biological questions. Moreover, the function visualize enrichment (i.e. colocalization) directly in the images for easy interpretation. We demonstrate the approachs functionality on both simulated data and cultured neurons, and compare it to current alternative measures. The method is available in a Python function for easy and parameter-free implementation.

cell biology↗

bioRxiv2021

Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2-autoreceptor activity

The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show by application of several super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the dopamine transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and by DA D2-autoreceptor activation in manner dependent on Ca2+-influx via N-type voltage-gated Ca2+-channels. The DAT nanodomains contain tens of transporters molecules and overlap with nanodomains of PIP2 (phosphatidylinositol-4,5-bisphosphate) but show little overlap with D2-autoreceptor, syntaxin-1 and clathrin nanodomains. Summarized, the data reveal a mechanism for rapid alterations in nanoscopic DAT distribution and show a striking link of this to the conformational state of the transporter.

neuroscience↗