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.

The dorsomedial prefrontal cortex (dmPFC) and basal ganglia (BG) are tightly interconnected through cortico-BG-thalamocortical (CBGT) loops that undergo extensive refinement during postnatal development. While the role of cortical activity in shaping striatal circuit maturation is well established, the extent to which the BG regulate dmPFC development remains unclear. Here, we examined whether early striatal output influences the maturation of dmPFC activity and connectivity. Targeted ablation of direct or indirect pathway spiny projection neurons during the first two postnatal weeks induced bidirectional changes in dmPFC neural activity akin to BG modulation of cortical dynamics observed in mature circuits. Interestingly, these manipulations also disrupted synaptic maturation of layer 2/3 pyramidal neurons, shifting the balance between excitation and inhibition. Together, these findings demonstrate that striatal output regulates cortical activity during early postnatal development and suggest a previously unrecognized role for the BG in guiding the establishment of prefrontal cortical networks.

Age-related cognitive decline in learning and decision-making may arise from increased variability of neural responses. Here, we investigated how ageing affects behavioral and neural variability by recording >18,000 neurons across 16 brain regions (including cortex, hippocampus, thalamus, midbrain, and basal ganglia) in younger and older mice performing a visual decision-making task. Older mice showed more variable response times, reproducing a common finding in human ageing studies. Ageing globally increased firing rates, post-stimulus neural variability (quantified using the Fano Factor), and decreased 'variability quenching' (the reduction in neural variability upon stimulus presentation). Older animals showed higher overall firing rates across areas of visual and motor cortex, striatum, midbrain, and hippocampus, but lower firing rates in thalamic areas. Age-related attenuation in stimulus-induced variability quenching was most prominent in visual and motor cortex, striatum, and thalamic area. These findings show how large-scale neural recordings can help uncover regional specificity of ageing effects in single neurons, improving our understanding of the neural basis of age-related cognitive decline.

Parkinson's disease (PD) is characterized by progressive neurodegeneration, which is associated with motor and non-motor symptoms. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), characterized by pathological gambling, hypersexuality, and/or compulsive shopping. Approximately 14-40% of all medicated PD patients suffer from ICD. Despite the high prevalence of ICD in medicated PD patients, we know little of its mechanisms, and the main therapeutic strategy is reducing or eliminating dopamine agonist medication. Human imaging studies suggest that the input nucleus of the basal ganglia, the striatum, may be a critical site of circuit dysfunction in ICD. To explore the cellular and circuit mechanisms of ICD, we developed a mouse model in which we administered the dopamine D2/3 agonist pramipexole to parkinsonian and healthy control mice. ICD-like behavior was assessed using a delay discounting task. Delay discounting is a normal cognitive phenomenon, in which the value of a reward decreases according to the time needed to wait for it. Impulsivity is measured as the preference for immediate (small) over delayed (large) rewards. We combined this mouse model with chemogenetics and in vivo optically-identified single-unit recordings to examine how dopamine agonists act on vulnerable striatal circuitry to mediate impulsive decision-making. We found that in parkinsonian mice, therapeutic doses of dopamine D2/3R or D1R agonists drove more pronounced delay discounting, reminiscent of what has been reported in PD/ICD patients on medication. In contrast, healthy mice did not become more impulsive when given the same dose of dopamine agonist. The clinically relevant dopamine D2/3R agonist pramipexole induced marked bidirectional changes in the firing of striatal direct and indirect pathway neurons in parkinsonian mice. Chronic pramipexole treatment potentiated these changes in striatal physiology and decision-making behavior. Furthermore, chemogenetic excitation of direct pathway striatal neurons or inhibition of indirect pathway neurons induced impulsive decision making in the absence of dopamine agonists. These findings indicate that abnormal striatal activity plays a causal role in mediating ICD-like behaviors. Together, they provide a robust mouse model and insights into ICD pathophysiology.

Repetitive behaviors are cardinal features of many brain disorders, including autism spectrum disorder (ASD). We previously associated dysfunction of striatal cholinergic interneurons (SCINs) with repetitive behaviors in a mouse model based on conditional deletion of the ASD-related gene Tshz3 in cholinergic neurons (Chat-cKO). Here, we provide evidence linking SCIN abnormalities to the unique organization of the striatum into striosome and matrix compartments, whose imbalances are implicated in several pathological conditions. Chat-cKO mice exhibit an altered relationship between the embryonic birthdate of SCINs and their adult striosome-matrix distribution, leading to an increased proportion of striosomal SCINs. In addition, the ratio of striosomal SCINs with slow-irregular vs. sustained-regular firing is increased, which translates into decreased activity, further stressing the striosome-matrix imbalance. These findings provide novel insights into the pathogenesis of ASD-related stereotyped behaviors by pointing to abnormal developmental compartmentalization and activity of SCINs as a substrate.

Cell transplantation offers a promising approach for treating Parkinson's disease (PD), but the limited survival of transplanted cells remains a major challenge. Reactive astrocytes, abundant in PD brains, may exacerbate this issue. GLP1R agonists, like semaglutide, are shown to inhibit reactive astrocytes in PD models. This study explores whether semaglutide could enhance the survival of transplanted neural stem cells (NSCs) in PD treatment. Six-hydroxydopamine-induced PD mouse models are used, with midbrain-derived NSCs transplanted into the lesioned striatum. Semaglutide is administered every other day for four weeks. In vivo imaging tracks the survival and distribution of DiD-labeled NSCs, while differentiation and astrocyte phenotypic changes are examined. Results show that semaglutide combined with NSC transplantation improves motor function. The mean fluorescence photon flux of mice transplanted with DiD-labeled NSCs alone is 0.8192 × 10, compared to 3.258 × 10 in those receiving both semaglutide and NSCs. Additionally, semaglutide reduces C3 reactive astrocytes (previously A1 reactive astrocytes) in the striatum. Co-culture experiments indicate that C3 reactive astrocytes hinder NSCs differentiation. RNA-seq reveals enriched inflammatory factors in C3 astrocytes. Semaglutide combined with NSCs transplantation may enhance PD treatment partly by inhibiting C3 reactive astrocytes and promoting the survival and differentiation of transplanted cells.