To navigate dynamic environments, animals must rapidly integrate sensory information and respond appropriately to gather rewards and avoid threats. It is well established that dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SNc) are key for creating associations between environmental stimuli (i.e., cues) and the outcomes they predict. Critically, it remains unclear how sensory information is integrated into dopamine pathways. The superior colliculus (SC) receives direct visual input and is positioned as a relay for dopamine neuron augmentation. We characterized the anatomy and functional impact of SC projections to the VTA/SNc in male and female rats. First, we show that neurons in the deep layers of SC synapse densely throughout the ventral midbrain, interfacing with projections to the striatum and ventral pallidum, and these SC projections excite dopamine and GABA neurons in the VTA/SNc in vivo. Despite this, cues predicting SC→VTA/SNc neuron activation did not reliably evoke behavior in an optogenetic Pavlovian conditioning paradigm, and activation of SC→VTA/SNc neurons did not support primary reinforcement or produce place preference/avoidance. Instead, we find that stimulation of SC→VTA/SNc neurons evokes head turning. Focusing optogenetic activation solely onto dopamine neurons that receive input from the SC was sufficient to invigorate turning, but not reinforcement. Turning intensity increased with repeated stimulations, suggesting that this circuit may underlie sensorimotor learning for exploration and attentional switching. Together, our results show that collicular neurons contribute to cue-guided behaviors by controlling pose adjustments through interaction with dopamine neurons that preferentially engage movement instead of reward. In dynamic environments, animals must rapidly integrate sensory information and respond appropriately to survive. Dopamine (DA) neurons are key for creating associations between environmental cues through learning, but it remains unclear how relevant sensory information is integrated into DA pathways to guide this process. The superior colliculus (SC) is positioned for rapid sensory augmentation of dopamine neurons. Using a combination of approaches, we find that SC neurons projecting to the ventral midbrain activate dopamine neurons and drive postural changes without creating conditioned behavior or valence. Our results highlight a brain circuit that is important for guiding movement to redirect attention, via interaction with classic learning systems, and suggest distinct subpopulations of dopamine neurons preferentially engage movement instead of reward.

Foraging and food consumption are fundamental for the survival of animals. In natural environments, wild rodents feed on insects, including moth larvae, and odor-guided evaluation of potential food resources is a critical step in initiating feeding behavior. However, the mechanisms by which rodents seek and feed on insect prey remain poorly understood. Herein, we employed a laboratory-based predator-prey interaction system using mice and cotton bollworm larvae to investigate the neural mechanisms underlying food-seeking and feeding behaviors at both cellular and neural circuit levels. We demonstrate that mice exhibit a strong preference for consuming fed larvae, and this preference is dependent on the main olfactory system. Gas chromatography-mass spectrometry analysis revealed significant differences in the chemical profiles of fed and unfed larvae, with fed larvae containing a higher level of linoleic acid (LA) and a lower level of (Z)-9-tricosene [(Z)-9-TE]. Behavioral assays showed that mice, as well as Brand's voles and brown rats, are attracted to LA but avoid (Z)-9-TE in a two-choice odor preference test. Furthermore, we identified that the dopaminergic pathway from the ventral tegmental area (VTA) to the medial olfactory tubercle (mOT) plays a central role in mediating this preference. Chemogenetic inhibition of this pathway abolished the preference for LA over (Z)-9-TE, while chemogenetic activation reversed this effect. Additionally, fiber photometry recordings and pharmacology revealed that mOT D1 and D2 spiny projection neurons preferentially mediate attraction to LA and avoidance of (Z)-9-TE, respectively. These findings uncover a neurobiological system in rodents that supports insect predation based upon chemosignals.

Dysfunction of the basal ganglia is implicated in a wide range of neurological and psychiatric disorders. Our understanding of the operation of the basal ganglia is largely derived on data from studies conducted on mice, which are frequently used as model organisms for various clinical conditions. The striatum, the largest compartment of the basal ganglia, consists of 90-95% striatal projection neurons (SPNs). It is therefore crucial to establish if human and mouse SPNs have distinct or similar properties, as this has implications for the relevance of mouse models for understanding the human striatum. To address this, we compared the general organization of the somato-dendritic tree of SPNs, the dimensions of the dendrites, the density and size of spines (spine surface area), and ion channel subtypes in human and mouse SPNs. Our findings reveal that human SPNs are significantly larger, but otherwise the organisation of the dendritic tree (dendrogram) with an average of approximately 5 primary dendrites, is similar in both species. Additionally in both humans and mice, over 90% of the spines are located on the terminal branches of each dendrite. Human spines are somewhat larger (4.3 versus 3.1 μm2) and the terminal dendrites have a uniform diameter in both humans and mice, although somewhat broader in the latter (1.0 versus 0.6 μm). The composition of ion channels is also largely conserved. These data have been used to simulate human SPNs building on our previous detailed simulation of mouse SPNs. We conclude that the human SPNs essentially appear as enlarged versions of the mouse SPNs. This similarity suggests that both species process information in a comparable manner, supporting the relevance of mouse models for studying the human striatum.

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.

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.

Sleep entails profound changes in the brain and body, marked by altered states of consciousness and reduced somatic and autonomic motor activity. Regarding "how" sleep is regulated, whole-brain screening revealed large sleep-control networks spanning the forebrain, midbrain, and hindbrain. We unify diverse experimental evidence under a "motor theory," in which the sleep-control mechanism is integral to somatic and autonomic motor circuits. Regarding the "why" question, sleep deprivation impairs cognition, emotion, metabolism, and immunity. We propose catecholamine (dopamine, noradrenaline, and adrenaline) inactivation as the fundamental biological process underlying sleep's numerous benefits. Beyond brain arousal and motor activity, catecholamines regulate metabolism and immunity; their sleep-dependent suppression yields wide-ranging advantages, promoting repair and rejuvenation. Furthermore, catecholaminergic neurons are metabolically vulnerable; their need for rest and recovery may drive homeostatic sleep pressure. Together, the motor theory offers a unifying framework for sleep control, while the catecholamine hypothesis posits a core mechanism mediating sleep's multifaceted benefits.

Dopaminergic neurons (DANs) in the substantia nigra pars lateralis (SNL) project to the tail of striatum, where they contribute to threat behaviors. Auditory cortex contributes to threat conditioning, but whether it directly modulates DANs is unclear. Here, we show that SNL DANs fire irregularly, achieve rapid maximal firing rates, exhibit distinct ionic conductances, and receive predominantly excitatory input. This contrasts with substantia nigra pars compacta (SNc) DANs that fire regularly and receive mainly inhibitory input, establishing SNL DANs as a physiologically distinct dopaminergic subpopulation. Functional mapping revealed robust excitatory input from auditory and temporal association cortices to SNL DANs, but not SNc DANs. In behavioral experiments, inhibiting neurotransmitter release from either SNL DANs or cortical afferents to SNL resulted in impaired auditory threat conditioning. Thus, our work reveals robust functional corticonigral projections to SNL DANs which directly regulate threat behaviors.

Dopamine midbrain (DA) neurons are involved in a wide array of key brain functions including movement control and reward-based learning. They are also critical for major brain disorders such as Parkinson Disease or schizophrenia. DA neurons projecting to distinct striatal territories are diverse with regards to their molecular makeup and cellular physiology, which are likely to contribute to the observed differences in temporal dopamine dynamics. Among these regions, the dorsolateral striatum (DLS) displays the fastest dopamine dynamics, which might control the moment-to-moment vigor and variability of voluntary movements. However, the underlying mechanisms for these DLS-specific fast DA fluctuations are unresolved. Here, we show that DLS-projecting DA neurons in the substantia nigra (SN) possess a unique biophysical profile allowing immediate 10-fold accelerations in discharge frequency via rebound bursting. By using a combination of patch-clamp recordings in projection-defined DA SN subpopulations from adult male mice and developing matching projection-specific computational models, we demonstrate that a strong interaction of Ca3 and SK channels specific for DLS-projecting Aldh1a1-positive DA SN (DLS-DA) neurons controls the gain of fast rebound bursting, while K4 and HCN channels mediate timing of rebound excitability. In addition, GIRK channels activated by D2- and GABA-receptors prevent rebound bursting in these DLS-DA neurons. Furthermore, our in vivo patch-clamp recordings and matching in vivo computational models provide evidence that these unique rebound properties might be preserved in the intact brain, where they might endow specific computational properties well suited for the generation of fast dopamine dynamics present in the dorsolateral striatum. DLS-projecting DA neurons in the SN exhibit unique rebound bursting that enables rapid, 10-fold increases in firing frequency. This firing fingerprint is driven by Ca3 and SK channel interactions, modulating burst gain, and fine-tuned by K4 and HCN channels controlling rebound timing. GIRK channels, activated by D2- and GABA-receptors, inhibit this bursting. In vivo patch-clamp recordings provide evidence that these rebound dynamics might be preserved in the intact brain, potentially supporting the fast dopamine fluctuations crucial for controlling movement vigor and variability in the DLS. These findings provide insights into the mechanisms underlying fast DA dynamics and their role in motor function, with implications for brain disorders like Parkinson disease and schizophrenia.

Similar to motor skill learning in mammals, vocal learning in songbirds requires a set of interconnected brain areas that make up an analogous basal ganglia-thalamocortical circuit known as the anterior forebrain pathway (AFP). Although neural activity in the AFP has been extensively investigated during awake singing, very little is known about its neural activity patterns during other behavioral states. Here, we used chronically implanted Neuropixels probes to investigate spontaneous neural activity in the AFP during natural sleep and awake periods in male zebra finches. We found that during sleep, neuron populations in the pallial region LMAN (lateral magnocellular nucleus of the nidopallium) spontaneously exhibited synchronized bursts that were characterized by a negative sharp deflection in the local field potential (LFP) and a transient increase in gamma power. LMAN population bursts occurred primarily during non-rapid eye movement (NREM) sleep and were highly reminiscent of sharp-wave ripple (SWR) activity observed in rodent hippocampus. We also examined the functional connectivity within the AFP by calculating the pairwise LFP coherence. As expected, delta and theta band coherence within LMAN and Area X was higher during sleep compared to awake periods. Contrary to our expectations, we did not observe strong coherence between LMAN and Area X during sleep, suggesting that the input from LMAN into Area X is spatially restricted. Overall, these results provide the first description of spontaneous neural dynamics within the AFP across behavioral states. Although cortical and basal ganglia circuits are known to be required for learning in both mammals and birds, little is known about the ongoing spontaneous activity patterns within these circuits, or how they are modulated by behavioral state. Here we prove the first description of cortical-basal ganglia network activity during sleep and awake periods in birds. Within the pallial area LMAN, we observed population-wide bursting events that were highly reminiscent of hippocampal sharp-wave ripple (SWR) activity, suggesting that large-scale population events have diverse functions across vertebrates.

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs-and optical activation of striatonigral neurons in particular-reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

A long-standing question in biology and medicine concerns how astrocytes influence neurons. Here, progress concerning how astrocytes affect neurons and neural circuits is summarized by focusing on data and concepts from studies of the striatum, which has emerged as a model nucleus. Mechanisms broadly applicable across brain regions and disorders are emphasized, and knowledge gaps are described. Experiments spanning multiple scales of biology show that astrocytes regulate neural circuits by virtue of homeostatic signaling and through astrocyte-neuron interactions. During disease, astrocytes contribute to nervous system malfunction in context-specific ways through failures of normal functions and the development of maladaptive responses. As ideally positioned endogenous cellular neuromodulators, astrocytes can be targeted for strategies to regulate neural circuits in brain disorders. After a historically slow start for the field, astrocyte-neuron interactions are now recognized as consequential for physiology and behavior, critically involved in pathophysiology, and exploitable in disease.

Dynamic signaling by extracellular and intracellular molecules impacts downstream pathways in a cell-type-specific manner. Fluorescent reporters of such signals are typically optimized to detect fast, relative changes in concentration of target molecules. They are less well suited to detect slowly changing signals and rarely provide absolute measurements. Here, we developed fluorescence lifetime photometry at high temporal resolution (FLIPR), which utilizes frequency-domain analog processing to measure the absolute fluorescence lifetime of genetically encoded sensors at high speed but with long-term stability and picosecond precision. We applied FLIPR to investigate dopamine signaling in functionally distinct striatal subregions. We observed higher tonic dopamine levels in the tail of the striatum compared with the nucleus accumbens core and differential and dynamic responses in phasic and tonic dopamine to appetitive and aversive stimuli. Thus, FLIPR reports fast and slow timescale neuronal signaling in absolute units, revealing previously unappreciated spatial and temporal variation even in well-studied signaling systems.

Action control is hypothesized to be mediated by corticothalamo-basal ganglia loops subserving the acquisition and updating of action contingencies. Within this, the mediodorsal thalamus (MD) is thought to contribute to volitional control over behavior largely through its interactions with prefrontal cortex. However, MD also projects into striatum, the main input nucleus of the basal ganglia, and the contribution of such projections to behavioral control is not known. Using a mouse model of volitional action control in either sex, here we find that MD terminal calcium activity in dorsal medial striatum (MD-DMS) represents action information during initial acquisition of a novel action contingency. This representation of action information decreases with continued experience. Data demonstrate MD-DMS activity is necessary to learn and employ a contingency control over actions. Functional attenuation of MD-DMS activity negated normal exploration, instead biasing repetitive action control, and resulted in mice unable to adapt their initial action strategy upon changes in action contingency. This suggests MD supports plasticity underlying initial action strategy learning used to adjust control given changing contingencies. Overall, these data show that MD projections into striatum contribute to volitional action control that supports acquisition of adaptive behavior. Mediodorsal (MD) thalamus is hypothesized to support volitional action control. However, focus has largely been on MD input into prefrontal cortical regions and the contribution of MD input to striatum has not been explored. Here we show that MD input into dorsal medial striatum supports acquisition of goal-directed strategies and their control over actions.

Gain modulation allows neurons to dynamically adjust their responsiveness to inputs without changing selectivity. While well-characterized in sensory areas, its role in higher-order brain regions governing spatial navigation and memory is unclear. Here, we used all-optical methods in mice performing a spatial task to demonstrate that vasoactive-intestinal peptide (VIP)-expressing neurons selectively control the gain of place cells and other cell types in the retrosplenial cortex (RSC) through disinhibition. Optogenetic manipulation revealed that this disinhibition, while broadly affecting network activity, selectively amplifies in-field place cell activity, improving spatial coding accuracy. In contrast, VIP neurons in the hippocampus have minimal impact on place field gain. Notably, simulations indicate that the benefit of gain modulation for RSC place cells is large compared to hippocampal place cells due to their much higher out-of-field activity and, therefore, lower signal-to-noise ratio. Here, we show an area-specific VIP-mediated gain control, enhancing spatial coding and, potentially, memory formation.

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.