Abstract: Background/Objectives: Learning is classically modeled to consist of an acquisition period followed by a mastery period when the skill no longer requires conscious control and becomes automatic. Dopamine neurons projecting to the ventral striatum (VS) produce a teaching signal that shifts from responding to rewarding or aversive events to anticipating cues, thus facilitating learning. However, the role of the dopamine-receptive neurons in the ventral striatum, particularly in encoding decision-making processes, remains less understood. Methods: Here, we introduce an operant conditioning paradigm using open-source microcontrollers to train mice in three sequential learning phases. Phase I employs classical conditioning, associating a 5 s sound cue (CS) with a sucrose–water reward. In Phase II, the CS is replaced by a lever press as the requirement for reward delivery, marking an operant conditioning stage. Phase III combines these elements, requiring mice to press the lever during the CS to obtain the reward. We recorded calcium signals from direct pathway spiny projection neurons (dSPNs) in the VS throughout the three phases of training. Results: We find that dSPNs are specifically engaged when the mouse makes a decision to perform a reward-seeking action in response to a CS but are largely inactive during actions taken outside the CS. Conclusions: These findings suggest that direct pathway neurons in the VS contribute to decision-making in learned action–outcome associations, indicating a specialized role in initiating operant behaviors.. Read the full article at https://www.mdpi.com/3070628.

Abstract: Modern noise-cancelling headphones have significantly improved users' auditory experiences by removing unwanted background noise, but they can also block out sounds that matter to users. Machine learning (ML) models for sound event detection (SED) and speaker identification (SID) can enable headphones to selectively pass through important sounds; however, implementing these models for a user-centric experience presents several unique challenges. First, most people spend limited time customizing their headphones, so the sound detection should work reasonably well out of the box. Second, the models should be able to learn over time the specific sounds that are important to users based on their implicit and explicit interactions. Finally, such models should have a small memory footprint to run on low-power headphones with limited on-chip memory. In this paper, we propose addressing these challenges using HiSSNet (Hierarchical SED and SID Network). HiSSNet is an SEID (SED and SID) model that uses a hierarchical prototypical network to detect both general and specific sounds of interest and characterize both alarm-like and speech sounds. We show that HiSSNet outperforms an SEID model trained using non-hierarchical prototypical networks by 6.9 - 8.6 percent. When compared to state-of-the-art (SOTA) models trained specifically for SED or SID alone, HiSSNet achieves similar or better performance while reducing the memory footprint required to support multiple capabilities on-devic. Read the full article at https://doi.org/10.48550/arXiv.2303.07538.

Abstract: Dopamine neurotransmission in the striatum is central to many normal and disease functions. Ventral midbrain dopamine neurons exhibit ongoing tonic firing that produces low extrasynaptic levels of dopamine below the detection of conventional extrasynaptic cyclic voltammetry (∼10–20 nanomolar), with superimposed bursts that can saturate the dopamine uptake transporter and produce transient micromolar concentrations. The bursts are known to lead to marked presynaptic plasticity via multiple mechanisms, but analysis methods for these kinetic parameters are limited. To provide a deeper understanding of the mechanics of the modulation of dopamine neurotransmission by physiological, genetic, and pharmacological means, we present three computational models of dopamine release with different levels of spatiotemporal complexity to analyze in vivo fast-scan cyclic voltammetry recordings from the dorsal striatum of mice. The models accurately fit to cyclic voltammetry data and provide estimates of presynaptic dopamine facilitation/depression kinetics and dopamine transporter reuptake kinetics, and we used the models to analyze the role of synuclein proteins in neurotransmission. The models’ results support recent findings linking the presynaptic protein α-synuclein to the short-term facilitation and long-term depression of dopamine release, as well as reveal a new role for β-synuclein and/or γ-synuclein in the long-term regulation of dopamine reuptake. Read the full article at https://doi.org/10.1093/pnasnexus/pgad044.

Abstract: Sound-to-color synesthesia is a neurological condition in which people experience different colors and shapes when listening to music. We present an augmented reality application that aims to create an interactive synesthesia experience for non-synesthetes. In this application, users can visualize colors corresponding to each unique note in the 12-tone equal-temperament tuning system, and the auditory input can be selected from audio files or real-time microphone. A gestural hand-tracking interface allows users to paint the world space in visualized synesthetic colors.  Read the full article at https://ieeexplore.ieee.org/document/9757577.

Abstract: It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known whether these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse “Treadmill Training Task” that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut (DLC) and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained proficiency at running. In contrast, direct pathway activity in the DLS was similar throughout training. Pharmacological blockade of D1 dopamine receptors in these subregions during task performance demonstrated that dopamine neurotransmission in the direct pathway activity is necessary for efficient motor coordination learning. These results provide new tools to measure changes in fine motor skills with simultaneous recordings of brain activity and reveal fundamental features of the neuronal substrates of motor learning. Read the full article at https://doi.org/10.1523/ENEURO.0169-22.2022.  

Abstract: Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.  Read the full article at https://doi.org/10.1016/j.celrep.2023.112231.