Within-Mice Comparison of Microdialysis and Fiber Photometry-Recorded Dopamine Biosensor during Amphetamine Response.

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 optical techniques such as fiber photometry (FP), has introduced technologically distinct means of measuring neurotransmission.

Behavioral encoding across timescales by region-specific dopamine 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.

Biophysical Modeling of Dopaminergic Denervation Landscapes in the Striatum Reveals New Therapeutic Strategy.

Parkinson's disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete.

Insights into Parkinson's disease from computational models of the basal ganglia.

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.

A three-step reconstruction method for fluorescence molecular tomography based on compressive sensing.

Fluorescence molecular tomography (FMT) is a promising tool for real time in vivo quantification of neurotransmission (NT) as we pursue in our BRAIN initiative effort. However, the acquired image data are noisy and the reconstruction problem is ill-posed. Further, while spatial sparsity of the NT effects could be exploited, traditional compressive-sensing methods cannot be directly applied as the system matrix in FMT is highly coherent.

Unsupervised Idealization of Ion Channel Recordings by Minimum Description Length: Application to Human PIEZO1-Channels.

Researchers can investigate the mechanistic and molecular basis of many physiological phenomena in cells by analyzing the fundamental properties of single ion channels. These analyses entail recording single channel currents and measuring current amplitudes and transition rates between conductance states. Since most electrophysiological recordings contain noise, the data analysis can proceed by idealizing the recordings to isolate the true currents from the noise.

Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

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.

How compensation breaks down in Parkinson's disease: Insights from modeling of denervated striatum.

The bradykinesia and other motor signs of Parkinson's disease (PD) are linked to progressive loss of substantia nigra dopamine (DA) neurons innervating the striatum. However, the emergence of idiopathic PD is likely preceded by a prolonged subclinical phase, which may be masked by a variety of pre- and postsynaptic compensatory mechanisms. It is often considered self-evident that the signs of PD manifest only when nigrostriatal degeneration has proceeded to such an extent that putative compensatory mechanisms fail to accommodate the depletion of striatal DA levels.

Functionally Distinct Dopamine Signals in Nucleus Accumbens Core and Shell in the Freely Moving Rat.

Unlabelled: 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.

[Optogenetics brings hidden neural mechanisms into the light and could become a future therapy].

Optogenetics is an emergent technology that combines light-sensitive proteins derived from algae, so-called opsins, with genetics. Viral vectors encoding opsins are injected into selective brain regions whereby specific cell populations can be controlled with high precision light pulses delivered via implanted optical fibres. This review focuses on explaining basic principles of optogenetics and describes important insights into neuropsychiatric mechanisms provided by the technology.

Three mechanisms by which striatal denervation causes breakdown of dopamine signaling.

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.

Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling.

Dopamine (DA) D2-like autoreceptors are an important component of the DA system, but their influence on postsynaptic DA signaling is not well understood. They are, directly or indirectly, involved in drug abuse and in treatment of schizophrenia and attention deficit hyperactive disorder: DA autoreceptors influence the behavioral effect of cocaine and methylphenidate and may be the target of antipsychotic medications such as haloperidol. DA autoreceptors are active at two levels: Somatodendritic autoreceptors mainly influence firing rate of DA neurons, and presynaptic autoreceptors control release of neurotransmitter at axonal terminals.

Spreading dynamics of a functionalized polymer latex.

Functionalized polymer nanoparticles are used as binders for inorganic materials in everyday technologies such as paper and coatings. However, the functionalization can give rise to two opposing effects: It can promote adhesion via specific interactions to the substrate, but a high degree of functionalization can also hamper spreading on substrates. Here, we studied the spreading kinetics of individual functionalized vinyl acetate-co-ethylene polymer nanoparticles on inorganic substrates by atomic force microscopy (AFM) imaging.

Influence of phasic and tonic dopamine release on receptor activation.

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.

A methodology to study impactor particle reentrainment and a proposed stage coating for the NGI.

Background: Mass-weighted aerodynamic particle-size distribution (APSD) is a key attribute for pharmaceutical products developed to deliver drugs to or through the lungs. In development and quality control, APSD is primarily determined using multistage cascade impactors. For impactor techniques, particle reentrainment is critical because it may lead to an overestimation of the respirable fraction.

Dynamic strength of the interaction between lung surfactant protein D (SP-D) and saccharide ligands.

In order to investigate the dynamic strength of the interaction between lung surfactant protein D (SP-D) and different sugars, maltose, mannose, glucose, and galactose, we have used an atomic force microscope to monitor the interaction on a single molecule scale. The experiment is performed by measuring the rupture force when the SP-D-sugar bond is subjected to a continuously increasing force. Under these dynamic conditions, SP-D binds strongest to d-mannose and weakest to maltose and d-galactose.

Quantitative approach to small-scale nonequilibrium systems.

In a nanoscale system out of thermodynamic equilibrium, it is important to account for thermal fluctuations. Typically, the thermal noise contributes fluctuations, e.g.

Novel optical and statistical methods reveal colloid-wall interactions inconsistent with DLVO and Lifshitz theories.

We present an experimental method based on video microscopy to perform nanometer scale position detection of a micrometer bead in the direction along the propagation of the detection light. Using the same bead for calibration and detection significantly improves the in depth resolution in comparison to video microscopy methods from literature. This method is used together with an optical trap to measure interaction potentials between a glass surface and colloids made of polystyrene or silica at different electrolyte concentrations.

Improved axial position detection in optical tweezers measurements.

We investigate the axial position detection of a trapped microsphere in an optical trap by using a quadrant photodiode. By replacing the photodiode with a CCD camera, we obtain detailed information on the light scattered by the microsphere. The correlation of the interference pattern with the axial position displays complex behavior with regions of positive and negative interference.

The motion of a single molecule, the lambda-receptor, in the bacterial outer membrane.

Using optical tweezers and single particle tracking, we have revealed the motion of a single protein, the lambda-receptor, in the outer membrane of living Escherichia coli bacteria. We genetically modified the lambda-receptor placing a biotin on an extracellular site of the receptor in vivo. The efficiency of this in vivo biotinylation is very low, thus enabling the attachment of a streptavidin-coated bead binding specifically to a single biotinylated lambda-receptor.