Dorsomedial striatal neuroinflammation causes excessive goal-directed action control by disrupting astrocyte function.
Compulsive actions are typically thought to reflect the dominance of habits over goal-directed action. To investigate this, we mimicked the striatal neuroinflammation that is frequently exhibited in individuals with compulsive disorders in rats, by injecting the endotoxin lipopolysaccharide into the posterior dorsomedial striatum, and assessed the consequences for behavioural control. Surprisingly, this manipulation caused rats to acquire and maintain goal-directed actions under conditions that would otherwise produce habits. Immunohistochemical analyses indicated that these behaviours were a result of astrocytic proliferation. To probe this further, we chemogenetically activated the Gi-pathway in striatal astrocytes, which altered the firing properties of nearby medium spiny neurons and modulated goal-directed action control. Together, results show that striatal neuroinflammation is sufficient to bias action selection toward excessive goal-directed control via dysregulated astrocyte function. If translatable, our findings suggest that, contrary to conventional views, individuals with striatal neuroinflammation might be more prone to maladaptive goal-directed actions than habits, and future interventions should aim to restore appropriate action control.
Cholinergic modulation enables scalable action selection learning in a computational model of the striatum.
The striatum plays a central role in action selection and reinforcement learning, integrating cortical inputs with dopaminergic signals encoding reward prediction errors. While dopamine modulates synaptic plasticity underlying value learning, the mechanisms that enable selective reinforcement of behaviorally relevant stimulus-action associations-the structural credit assignment problem-remain poorly understood, especially in environments with multiple competing stimuli and actions. Here, we present a computational model in which acetylcholine (ACh), released by striatal cholinergic interneurons, acts as a channel-specific gating signal that restricts plasticity to brief temporal windows following action execution. The model implements a biologically plausible three-factor learning rule requiring presynaptic activity, postsynaptic depolarization, and phasic dopamine, with plasticity gated by cholinergic pauses that temporally align with behaviorally relevant events. This mechanism ensures that only synapses involved in the selected behavior are eligible for modification. Through systematic evaluation across tasks with distractors and contingency reversals, we show that ACh-gated learning promotes synaptic specificity, suppresses cross-channel interference, and yields increasingly competitive performance relative to Q-learning in complex tasks, reflecting the scalability of the proposed learning mechanism. Moreover, the model reveals distinct roles for striatal pathways: direct pathway (D1) neurons maintain stimulus-specific responses, while indirect pathway (D2) neurons are progressively recruited to suppress outdated associations during policy adaptation. These findings provide a mechanistic account of how coordinated cholinergic and dopaminergic signaling can support scalable and efficient reinforcement learning in the striatum, consistent with experimental observations of pathway-specific plasticity.
All-optical voltage interrogation for probing synaptic plasticity in vivo.
Measuring synaptic efficacy and defining the rules for induction of synaptic plasticity at identified connections in the mammalian brain is essential for understanding how synapses contribute to learning and memory. This requires new approaches to selectively evoke presynaptic activity and measure postsynaptic responses with high spatiotemporal resolution and high sensitivity over long periods in vivo. Here we develop an all-optical approach to probe synaptic plasticity at identified cerebellar synapses in awake, behaving mice. We developed and applied JEDI-2Psub, a genetically encoded voltage indicator with increased sensitivity around resting membrane potentials, to record subthreshold and suprathreshold activity in Purkinje cell (PC) dendrites while selectively activating their granule cell (GrC) inputs using optogenetics and their climbing fiber (CF) inputs using sensory stimulation. We measured synaptic potentials and complex spike signals across the dendrites of multiple neighboring PCs, enabling us to examine correlations in voltage signals within and between neurons. We show how pairing GrC activity with sensory-evoked CF inputs can trigger long-term plasticity of inhibitory responses in PCs. These results provide a blueprint for defining the rules for plasticity induction at identified synapses in awake animals during behavior.
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Basal Ganglia Advances
Basal Ganglia Advances is a collection highlighting research on the structure, function, and disorders of the basal ganglia. It features studies spanning neuroscience, clinical insights, and computational models, serving as a hub for advances in movement, cognition, and behavior.
Navigation & Localization
Work related to place tuning, spatial navigation, orientation and direction. Mainly includes articles on connectivity in the hippocampus, retrosplenial cortex, and related areas.
Progress in Voltage Imaging
Recent advances in the field of Voltage Imaging, with a special focus on new constructs and novel implementations.
Most Popular Recent Articles
Surprises From the Basal Ganglia: Stop and Go Have New Meaning.
This perspective highlights new work suggesting the need for revision of the canonical direct-indirect model of the basal ganglia's influence on movement, with fresh evidence that there is a formerly unappreciated pair of direct and indirect pathways that parallel the standard model's canonical direct and indirect pathways, and promising evidence pointing toward improved clinical treatments for Parkinson's disease. As a working hypothesis, it is suggested that the non-canonical direct and indirect pathways, which arise in striosomes, might act as homeostatic circuits that can reign in or amplify the activity of the canonical pathways in the face of their imbalance, including that occurring in hyperkinetic or hypokinetic disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
A whole-brain male mouse atlas of long-range inputs to histaminergic neurons.
The precise structural and functional characteristics of input circuits targeting histaminergic neurons remain poorly understood. Here, using a rabies virus retrograde tracing system combined with fluorescence micro-optical sectioning tomography, we construct a 3D monosynaptic long-range input atlas of male mouse histaminergic neurons. We identify that the hypothalamus, thalamus, pallidum, and hippocampus constitute major input sources, exhibiting diverse spatial distribution patterns and neuronal type ratios. Notably, a specific layer distribution pattern and co-projection structures of upstream cortical neurons are well reconstructed at single-cell resolution. As histaminergic system is classically involved in sleep-wake regulation, we demonstrate that the lateral septum (predominantly supplying inhibitory inputs) and the paraventricular nucleus of the thalamus (predominantly supplying excitatory inputs) establish monosynaptic connections, exhibiting distinct functional dynamics and regulatory roles in rapid-eye-movement sleep. Collectively, our study provides a precise long-range input map of mouse histaminergic neurons at mesoscopic scale, laying a solid foundation for future systematic study of histaminergic neural circuits.
Visual gamma stimulation induces 40 Hz neural oscillations in the human hippocampus and alters phase synchrony and lag.
Nonpharmaceutical approaches based on gamma entrainment using sensory stimuli (GENUS) have shown promise in reducing Alzheimer's disease pathology in mouse models. While human studies remain limited, GENUS has been shown to alleviate aspects of neurodegeneration in patients with Alzheimer's disease. In this study, we analyze intracranial EEG data from 490 contacts across eleven patients with refractory epilepsy in response to three visual stimulation conditions. We find that 40 Hz visual stimulation successfully entrains neural activity beyond early visual areas, including the hippocampus and other cortical regions such as the temporal and frontal lobes. Additionally, we show that synchronization increases between the hippocampus and other cortical areas in response to the 40 Hz visual stimulation. Furthermore, combining stimulation with a simple visual oddball task alters the direction of information flow from frontal regions to the hippocampus and enhances both the strength and spatial extent of neural entrainment. These findings highlight the potential influence of cognitive engagement during sensory gamma stimulation and provide additional insights into the neurophysiological effects of 40 Hz visual stimulation.