Thalamus orchestrates local acetylcholine-dependent dopamine release in the learning striatum.
Dopamine is essential for striatal function and learning. Striatal dopamine release can be triggered by dopamine cell firing, but also by coordinated cholinergic interneuron activity, which stimulates dopamine release via presynaptic nicotinic acetylcholine receptors on dopamine axons. While acetylcholine-dependent dopamine release is well-documented ex vivo and under artificial optogenetic stimulation in vivo, its role during natural behavior has remained unclear. One possible endogenous driver of acetylcholine-dependent dopamine release is thalamic input, which provides strong excitatory drive to cholinergic interneurons. To examine whether thalamic input provokes acetylcholine-dependent dopamine release during behavior, we performed simultaneous fiber photometry recordings of striatal dopamine (GRAB-rDA3m) and thalamic axon activity (gCaMP8m) in the dorsomedial (DMS) and dorsolateral striatum (DLS) of mice learning the accelerating rotarod, a striatal-dependent task that demands precise and effortful motor control. Recordings were obtained on- and off-task and across days of training to capture the full arc of learning. Dopamine transients in DMS, but not DLS, were frequently coupled to peaks in thalamic axon activity via an acetylcholine-dependent mechanism. The occurrence of these thalamic-evoked DMS dopamine transients depended on learning, task engagement, and the recent history of dopamine activity, but did not contribute to motor error signals. Together, these findings establish thalamic input as a physiological driver of acetylcholine-dependent dopamine release in DMS. Moreover, they reveal that striatal sensitivity to this local release mechanism is dynamically gated by dopaminergic history, providing a compelling framework for understanding how local and soma-triggered dopamine signals are coordinated to support learning.
Neuropixels Opto: combining high-resolution electrophysiology and optogenetics.
High-resolution extracellular electrophysiology is the gold standard for recording spikes from distributed neural populations and is especially powerful when combined with optogenetics for manipulation of specific cell types with high temporal resolution. We integrated these approaches into prototype Neuropixels Opto probes, which combine electronic and photonic circuits. These devices pack 960 electrical recording sites and two sets of 14 light emitters onto a 70-μm-wide, 1-cm-long shank, allowing spatially addressable optogenetic stimulation with blue and red light. In mouse cortex, Neuropixels Opto probes delivered high-quality recordings together with spatially addressable optogenetics, differentially activating or silencing neurons at distinct cortical depths. In the mouse striatum and other deep structures, Neuropixels Opto probes delivered efficient optotagging, facilitating the identification of two cell types in parallel. Neuropixels Opto probes represent a promising tool for recording, identifying and manipulating neuronal populations.
Dual neuromodulatory dynamics underlie birdsong learning.
Although learning in response to extrinsic reinforcement is theorized to be driven by dopamine signals that encode the difference between expected and experienced rewards, skills that enable verbal or musical expression can be learned without extrinsic reinforcement. Instead, spontaneous execution of these skills is thought to be intrinsically reinforcing. Whether dopamine signals similarly guide learning of these intrinsically reinforced behaviours is unknown. In juvenile zebra finches learning from an adult tutor, dopamine signalling in a song-specialized basal ganglia region is required for successful song copying, a spontaneous, intrinsically reinforced process. Here we show that dopamine dynamics in the song basal ganglia faithfully track the learned quality of juvenile song performance on a rendition-by-rendition basis. Furthermore, dopamine release in the basal ganglia is driven not only by inputs from midbrain dopamine neurons classically associated with reinforcement learning but also by song premotor inputs, which act by means of local cholinergic signalling to elevate dopamine during singing. Although both cholinergic and dopaminergic signalling are necessary for juvenile song learning, only dopamine tracks the learned quality of song performance. Therefore, dopamine dynamics in the basal ganglia encode performance quality during self-directed, long-term learning of natural behaviours.
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Most Popular Recent Articles
Using appreciative inquiry to co-design contextually responsive diagnostic practices for developmental language disorder in the Northern Territory in Australia.
This study explored the use of Appreciative Inquiry to engage speech-language pathologists in co-designing culturally and contextually responsive diagnostic practices for Developmental Language Disorder in the Northern Territory, Australia.
Embedded 3D Superionic Network Enables Pressure-Free Solid-State Sodium Batteries with Ultrafast Na Diffusivity over a Wide Temperature Range.
Rechargeable solid-state sodium-metal batteries (SSSMBs) are promising for next-generation energy storage, yet their performance severely deteriorates at ultralow temperatures due to interfacial degradation and sluggish bulk Na transport. The core issue lies in the low Na diffusivity within the anode, which induces interfacial void formation and nonuniform Na plating, triggering dendrite growth and rapid capacity fading. To fundamentally address this challenge, we designed an innovative composite anode by constructing an in situ 3D continuous superionic NaP network within the sodium anode. The engineered 3D superionic network can facilitate uniform Na stripping/plating along the ion-conducting backbone, which effectively stabilizes the solid-state interface against cyclic degradation and dramatically enhances the Na diffusivity to 8 × 10 cm s. Consequently, symmetric solid-state cells achieve an areal capacity of 14 mAh cm without stacking pressure; fascinatingly, full solid-state cells with this composite anode also demonstrate cyclic stability across a wide temperature range (-25 to 60 °C) and sustain over 540 cycles under a mass loading of 10 mg cm. This work highlights the superionic network integration as a practical strategy toward high-performance and extreme-temperature SSSMBs without stacking pressure, emphasizing the critical role of high atomic diffusivity in enabling durable, pressure-free solid-state batteries.
Transnasal Zolmitriptan-Ginkgolide B loaded liposomes for migraine therapy: formulation, optimisation and characterisation.
Migraine is a chronic neurological disorder that necessitates swift and efficient treatment. Zolmitriptan (ZMT) is a first-line agent with low oral bioavailability and a slow onset of action. Intranasal delivery represents one of the noninvasive routes, directly targeting the nose-to-brain pathway. Therefore, a nano-liposomal system for the co-encapsulation of Zolmitriptan and Ginkgolide B (GB) was developed for efficient intranasal synergistic migraine therapy. The preparation of co-loaded liposomes was performed by thin-film hydration and then optimized by means of DoE. The nanoparticles of the optimal formulation had a mean diameter of 73.13 ± 10.45 nm, high entrapment efficiencies for both ZMT and GB (94.88 ± 2.0% and 95.41 ± 1.3%, respectively) and a biphasic pattern of drug release: a fast burst release of ZMT during the first 2 hours (95.69 ± 4.58%), followed by sustained release of GB within 8 hours (cumulative amount of 98.37 ± 2.87%). The permeation study further demonstrated an increased transport across the olfactory mucosa compared to the control treatments. The formulation was well cytocompatible against the nasal cell line (>80% cell viability) and stable upon storage at refrigerated conditions. In this way, it is emphasized that this new dual-drug co-loaded liposomal system may be of great promise in providing improved migraine management through direct brain delivery, but needs experimentation.