Invasive electrophysiological recordings in subcortical structures of nonhuman primates typically involve implanting electrodes into the brain through a skull-mounted chamber. These electrodes may be attached to the chamber temporarily for hours of neural recording, or permanently for long-term studies. Current challenges involve maintaining asepsis and integrating dual-modality monitoring of both electrical and chemical neural activity.

We developed an implantable neural interface that provides such dual-modality monitoring in monkeys, while maintaining aseptic conditions for year-long periods. We leveraged osseointegrating materials and hermetic sealing strategies to prevent the transmission of pathogenic species, while preserving the modular functionality of chamber systems, such as sensor depth adjustability. The system also features an aspirating port for culturing chamber fluid to ensure continued asepsis.

Our chamber system was shown to provide successful recordings of dopamine and electrical neural activity in two monkeys while maintaining negative bacteria culture results for over a year post-implantation.

Sealed chamber systems prevent contamination and reduce the risk of compromising animal health by minimizing the accumulation of pathogenic organisms. Such sealed chambers also eliminate the need for frequent cleaning. However, neurochemical measurements require specialized electrodes with fragile carbon fiber tips and are not compatible with recently developed, sealed chamber systems.

This advanced chamber design builds upon traditional chamber protocols to enable chronic measurements of chemical and electrical neural activity. This approach facilitates novel ways to study the brain in behaving primates while prioritizing the long-term health and welfare of the animals.

Objective.Brain computer interfaces (BCIs) require substantial cognitive flexibility to optimize control performance. Remarkably, learning this control is rapid, suggesting it might be mediated by neuroplasticity mechanisms operating on very short time scales. Here, we propose a meta plasticity model of BCI learning and skill consolidation at the single cell and population levels comprised of three elements: (a) behavioral time scale synaptic plasticity (BTSP), (b) intrinsic plasticity (IP) and (c) synaptic scaling (SS) operating at time scales from seconds to minutes to hours and days. Notably, the model is able to explainrepresentational drift-a frequent and widespread phenomenon that adversely affects BCI control and continued use.Approach.We developed an all-optical approach to characterize IP, BTSP and SS with single cell resolution in awake mice using fluorescent two photon (2P) GCaMP7s imaging and optogenetic stimulation of the soma targeted ChRmineKv2.1. We further trained mice on a one-dimensional BCI control task and systematically characterized within session (seconds to minutes) learning as well as across sessions (days and weeks) with different neural ensembles.Main results.On the time scale of seconds, substantial BTSP could be induced and was followed by significant IP over minutes. Over the time scale of days and weeks, these changes could predict BCI control proficiency, suggesting that BTSP and IP might be complemented by SS to stabilize and consolidate BCI control.Significance.Our results provide early experimental support for a meta plasticity model of continual BCI learning and skill consolidation. The model predictions may be used to design and calibrate neural decoders with complete autonomy while considering the temporal and spatial scales of plasticity mechanisms. With the power of modern-day machine learning and artificial Intelligence, fully autonomous neural decoding and adaptation in BCIs might be achieved with minimal to no human intervention.

A hallmark of optimal reinforcement learning is that an agent learns to avoid actions that lead to negative outcomes while still exploring alternative actions that could lead to better outcomes. Although the basal ganglia have been hypothesized to contribute to this computation, the mechanisms by which they do so are still unclear. Here, we focus on the function of the striatal indirect pathway and propose that it is regulated by a synaptic plasticity rule that allows an animal to avoid actions that lead to suboptimal outcomes. We consider current theories of striatal indirect pathway function in light of recent experimental findings and discuss studies that suggest that indirect pathway activity is potentiated by the suppression of dopamine release in the striatum. Furthermore, we highlight recent studies showing that activation of the indirect pathway can trigger an action, allowing animals to explore new actions while suppressing suboptimal actions. We show how our framework can reconcile previously conflicting results regarding the indirect pathway and suggest experiments for future investigation.

Synaptic plasticity underlies learning by modifying specific synaptic inputs to reshape neural activity and behavior. However, the rules governing which synapses will undergo different forms of plasticity in vivo during learning and whether these rules are uniform within individual neurons remain unclear. Using in vivo longitudinal imaging with single-synapse resolution in the mouse motor cortex during motor learning, we found that apical and basal dendrites of layer 2/3 (L2/3) pyramidal neurons showed distinct activity-dependent synaptic plasticity rules. The strengthening of apical and of basal synapses is predicted by local coactivity with nearby synapses and activity coincident with postsynaptic action potentials, respectively. Blocking postsynaptic spiking diminished basal synaptic potentiation without affecting apical plasticity. Thus, individual neurons use multiple activity-dependent plasticity rules in a compartment-specific manner in vivo during learning.

The dopaminergic modulation of striatal circuit function remains intensely studied and debated. Nevertheless, a prevalent view is that striatal dopamine serves important roles in both reinforcement learning and the performance of movements, two highly distinct processes. But this dichotomy has led to a longstanding problem of how to interpret the functional consequences of a particular dopaminergic signal-is it to learn or to move? In order to explore this ambiguity and approach a possible resolution, this review examines the key evidence for dopamine's role in learning and movement. As part of that discussion, we consider a recent body of evidence that views the common dichotomous perspective through a more nuanced lens, by suggesting a comparatively limited dopaminergic contribution to movement. This concept, which we refer to as the learning primacy hypothesis, offers a unified conceptual framework for understanding dopaminergic function.

Dopamine modulates corticostriatal plasticity in both the direct and indirect pathways of the cortico-striato-thalamo-cortical (CSTC) loops. These gradual changes in corticostriatal synaptic strengths produce long-lasting changes in behavioral responses. Under normal conditions, these mechanisms enable the selection of the most appropriate responses while inhibiting others. However, under dysregulated dopamine conditions, including a lack of dopamine release or dopamine signaling, these mechanisms could lead to the selection of maladaptive responses and/or the inhibition of appropriate responses in an experience-dependent and task-specific manner. In this review, we propose that preventing or reversing such maladaptive synaptic strengths and erasing such aberrant "memories" could be a disease-modifying therapeutic strategy for many neurological and psychiatric disorders. We review evidence from Parkinson's disease, drug-induced parkinsonism, L-DOPA-induced dyskinesia, obsessive-compulsive disorder, substance use disorders, and depression as well as research findings on animal disease models. Altogether, these studies allude to an emerging theme in translational neuroscience and promising new directions for therapy development. Specifically, we propose that combining pharmacotherapy with behavioral therapy or with deep brain stimulation (DBS) could potentially cause desired changes in specific neural circuits. If successful, one important advantage of correcting aberrant synaptic plasticity is long-lasting therapeutic effects even after treatment has ended. We will also discuss the potential molecular targets for these therapeutic approaches, including the cAMP pathway, proteins involved in synaptic plasticity as well as pathways involved in new protein synthesis. We place special emphasis on RNA binding proteins and epitranscriptomic mechanisms, as they represent a new frontier with the distinct advantage of rapidly and simultaneously altering the synthesis of many proteins locally.

Dopamine neurons (DANs) play seemingly distinct roles in reinforcement, 1-3 motivation, 4,5 and movement, 6,7 and DA-modulating therapies relieve symptoms across a puzzling spectrum of neurologic and psychiatric symptoms. 8 Yet, the mechanistic relationship among these roles is unknown. Here, we show DA's tripartite roles are causally linked by a process in which phasic striatal DA rapidly and persistently recalibrates the propensity to move, a measure of vigor. Using a self-timed movement task, we found that single exposures to reward-related DA transients (both endogenous and exogenously-induced) exerted one-shot updates to movement timing-but in a surprising fashion. Rather than reinforce specific movement times, DA transients quantitatively changed movement timing on the next trial, with larger transients leading to earlier movements (and smaller to later), consistent with a stochastic search process that calibrates the frequency of movement. Both abrupt and gradual changes in external and internal contingencies-such as timing criterion, reward content, and satiety state-caused changes to the amplitude of DA transients that causally altered movement timing. The rapidity and bidirectionality of the one-shot effects are difficult to reconcile with gradual synaptic plasticity, and instead point to more flexible cellular mechanisms, such as DA-dependent modulation of neuronal excitability. Our findings shed light on how natural reinforcement, as well as DA-related disorders such as Parkinson's disease, could affect behavioral vigor.

Value-based decision-making relies on the striatum, where neural plasticity can be altered by chronic ethanol (EtOH) exposure, but the effects of such plasticity on striatal neural dynamics during decision-making remain unclear. This study investigated the long-term impacts of EtOH on reward-driven decision-making and striatal neurocomputations in male and female rats using a dynamic probabilistic reversal learning task. Following a prolonged withdrawal period, EtOH-exposed male rats exhibited deficits in adaptability and exploratory behavior, with aberrant outcome-driven value updating that heightened preference for chosen action. These behavioral changes were linked to altered neural activity in the dorsomedial striatum (DMS), where EtOH increased outcome-related encoding and decreased choice-related encoding. In contrast, female rats showed minimal behavioral changes with distinct EtOH-evoked alterations of neural activity, revealing significant sex differences in the impact of chronic EtOH. Our findings underscore the impact of chronic EtOH exposure on adaptive decision-making, revealing enduring changes in neurocomputational processes in the striatum underlying cognitive deficits that differ by sex.

Animals can learn to associate a behavior or a stimulus with a delayed reward, this is essential for survival. A mechanism proposed for bridging this gap are synaptic eligibility traces, which are slowly decaying tags, which can lead to synaptic plasticity if followed by rewards. Recently, experiments have demonstrated the existence of synaptic eligibility traces in diverse neural systems, depending on either neuromodulators or plateau potentials. Evidence for both eligibility trace-dependent potentiation and depression of synaptic efficacies has emerged. We discuss the commonalities and differences of these different results. We show why the existence of both potentiation and depression is important because these opposing forces can lead to a synaptic stopping rule. Without a stopping rule, synapses would saturate at their upper bound thus leading to a loss of selectivity and representational power. We discuss the possible underlying mechanisms of the eligibility traces as well as their functional and theoretical significance.

Even in the absence of external stimuli, the brain is spontaneously active. Indeed, most cortical activity is internally generated by recurrence. Both theoretical and experimental studies suggest that chaotic dynamics characterize this spontaneous activity. While the precise function of brain chaotic activity is still puzzling, we know that chaos confers many advantages. From a computational perspective, chaos enhances the complexity of network dynamics. From a behavioural point of view, chaotic activity could generate the variability required for exploration. Furthermore, information storage and transfer are maximized at the critical border between order and chaos. Despite these benefits, many computational brain models avoid incorporating spontaneous chaotic activity due to the challenges it poses for learning algorithms. In recent years, however, multiple approaches have been proposed to overcome this limitation. As a result, many different algorithms have been developed, initially within the reservoir computing paradigm. Over time, the field has evolved to increase the biological plausibility and performance of the algorithms, sometimes going beyond the reservoir computing framework. In this review article, we examine the computational benefits of chaos and the unique properties of chaotic recurrent neural networks, with a particular focus on those typically utilized in reservoir computing. We also provide a detailed analysis of the algorithms designed to train chaotic RNNs, tracing their historical evolution and highlighting key milestones in their development. Finally, we explore the applications and limitations of chaotic RNNs for brain modelling, consider their potential broader impacts beyond neuroscience, and outline promising directions for future research.

Responding appropriately to potential threats before they materialize is critical to avoiding disastrous outcomes. Here we examine how threat-coping behavior is regulated by the tail of the striatum (TS) and its dopamine input. Mice were presented with a potential threat (a moving object) while pursuing rewards. Initially, the mice failed to obtain rewards but gradually improved in later trials. We found that dopamine in TS promoted avoidance of the threat, even at the expense of reward acquisition. Furthermore, the activity of dopamine D1 receptor-expressing neurons promoted threat avoidance and prediction. In contrast, D2 neurons suppressed threat avoidance and facilitated overcoming the potential threat. Dopamine axon activation in TS not only potentiated the responses of dopamine D1 receptor-expressing neurons to novel sensory stimuli but also boosted them acutely. These results demonstrate that an opponent interaction of D1 and D2 neurons in the TS, modulated by dopamine, dynamically regulates avoidance and overcoming potential threats.

With increasing feedback delay, feedback processing appears to shift from the striatum to the hippocampus. In addition, higher-order sensory areas might be involved in bridging a temporal gap between stimulus and feedback by reactivating the representation of the feedback-predicting stimulus during feedback processing. We hypothesized that the feedback-locked N170, an occipito-temporal event-related potential (ERP) component linked to higher-order visual processing, is more pronounced when delayed feedback is provided for choices between visual compared to auditory stimuli. 35 subjects completed a probabilistic feedback learning task with immediate (1 s) and delayed (7 s) monetary feedback for choices between visual or auditory stimuli. Participants successfully learned to choose the more rewarding stimuli irrespective of stimulus modality. For the N170 amplitude over the right hemisphere, we found an interaction between feedback timing and the modality of the chosen stimulus. Only for delayed feedback, the N170 was more pronounced for choices between visual than auditory stimuli. Moreover, in this condition, the N170 amplitude particularly reflected the reward prediction error (PE), with larger amplitudes for positive PEs and lower amplitudes for negative PEs. This suggests that the N170 reflects feedback-locked reactivations in higher-order visual areas mediated by the reward PE. While these effects need to be studied further, we discuss the N170 as a counterpart to the feedback-related negativity (FRN) regarding interacting influences of feedback valence, feedback timing, and PE.

Recent findings show that stereotyped movement sequences (habits) need the cortex in the learning phase, but after learning, the cortex can be inactivated, and the movement still be performed flawlessly. The motor program is dependent on the sensorimotor part of the dorsolateral striatum (DLS) and on synaptic plasticity in the thalamostriatal synapses. New findings from several laboratories have revealed a highly precise spatially interactive organization within the basal ganglia [DLS, substantia nigra pars reticulata (SNr), and the thalamostriatal parafascicular nucleus (PF)] and with precise input from the cortex. The DLS-SNr-PF-DLS loop is subdivided into many parallel loops. I now propose that these parallel loops can act to reinforce the activity of the different striatal projection neurons in the DLS that take part and that the synaptic transmission in DLS becomes potentiated each time the motor sequence is performed successfully, if rewarded through a dopamine burst. It is argued that after learning the DLS-SNr-PF-DLS loop can operate in isolation.

Cerebrovascular accident (CVA) or stroke is a devastating neurological condition with dismal prognosis associated with recurrent episodes that further damage the neuronal networks, thus disabling neuronal plasticity. Vagus nerve stimulation (VNS) has been used in clinical practice to treat epilepsy for several decades and is well accepted as a safe procedure devoid of serious adverse events. Bailey and Bremer demonstrated that VNS has the capabilities to stimulate neuronal pathways that enhance the recovery of damaged cerebral function. Further studies have strengthened these observations, while technology has improved the tolerability of implants, resulting in VNS applications for epilepsy. Several animal models on neural plasticity have improved our understanding of VNS and its ability to provide neuromodulation to improve recovery in stroke patients. The closed-loop stimulation of the vagus nerve with individualized stimulation parameters combined with physical therapy appears to be an attractive option today. VNS is also being tested as a noninvasive trans-cutaneous modality to further improve patient acceptance and tolerability. However, the implantation of VNS is yielding desirable outcomes and appears to be a more reliable treatment for stroke rehabilitation in clinical trials.

The nucleus accumbens (NAc) helps govern motivation to pursue reward. Two distinct sets of NAc projection neurons-expressing dopamine D1 vs. D2 receptors-are thought to promote and suppress motivated behaviors, respectively. However, support for this conceptual framework is limited: in particular, the spiking patterns of these distinct cell types during motivated behavior have been largely unknown. Using optogenetic tagging, we recorded the spiking of identified D1+ and D2+ neurons in the NAc core as unrestrained rats performed an operant task in which motivation to initiate work tracks recent reward rate. D1+ neurons preferentially increased firing as rats initiated trials and fired more when reward expectation was higher. By contrast, D2+ cells preferentially increased firing later in the trial, especially in response to reward delivery-a finding not anticipated from current theoretical models. Our results provide new evidence for the specific contribution of NAc D1+ cells to self-initiated approach behavior and will spur updated models of how D2+ cells contribute to learning.

Timed dopamine signals underlie reinforcement learning, favoring neural activity patterns that drive behaviors with positive outcomes. In the striatum, dopamine activates five dopamine receptors (D1R-D5R), which are differentially expressed in striatal neurons. However, the role of specific dopamine receptors in reinforcement is poorly understood. Using our cell-specific D1R photo-agonist, we find that D1R activation in D1-expressing neurons in the dorsomedial striatum is sufficient to reinforce preceding neural firing patterns in defined ensembles of layer 5 cortico-striatal neurons of the mouse motor cortex. The reinforcement is cumulative and time dependent, with an optimal effect when D1R activation follows the selected neural pattern after a short interval. Our results show that D1R activation in striatal neurons can selectively reinforce cortical activity patterns, independent of a behavioral outcome or a reward, crucially contributing to the fundamental mechanisms that support cognitive functions like learning, memory, and decision-making.

The striatum consists of two anatomically and neurochemically distinct compartments, striosomes and the matrix, which receive dopaminergic inputs from the midbrain and exhibit distinct dopamine release dynamics in acute brain slices. Striosomes comprise approximately 15 % of the striatum by volume and are distributed mosaically. Therefore, it is difficult to selectively record dopamine dynamics in striosomes using traditional neurochemical measurements in behaving animals, and it is unclear whether distinct dynamics play a role in associative learning. In this study, we used transgenic mice selectively expressing Cre in striosomal neurons, combined with a fiber photometry technique, to selectively record dopamine release in striosomes during classical conditioning. Water-restricted mice could distinguish the conditioned stimulus (CS) associated with saccharin water from the air-puff-associated CS. The air-puff-associated CS evoked phasic dopamine release only in striosomes. Furthermore, air puff presentation induced dopamine release to striosomal neurons but suppressed release to striatal neurons non-selectively recorded. These findings suggest that dopamine is released in a differential manner in striosomes and the matrix in behaving animals and that dopamine release in striosomes is preferentially induced by the air-puff-associated CS and air puff presentation. These findings support the hypothesis that striosomal neurons play a dominant role in aversive stimuli prediction.

Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards-an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2, but little is known about whether, where and how neurons in this circuit encode information about higher-order moments of reward distributions3. Here, to fill this gap, we used high-density probes (Neuropixels) to record striatal activity from mice performing a classical conditioning task in which reward mean, reward variance and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons-D1 and D2-contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 medium spiny neurons4-9 to reap the computational benefits of distributional RL.

We developed an implantable neural interface for monitoring both chemical and electrical forms of brain activity in monkeys that maintains aseptic properties for year-long periods while leveraging the modular functions (e.g., sensor moveability) provided by a chamber system. Invasive electrophysiological recordings, especially in subcortical structures from nonhuman primates usually involves implanting electrodes into the brain through a skull-mounted chamber. These electrodes may be attached temporarily for several hours of recording, or permanently. Permanent attachments are favorable to allow for sealing the chamber completely from externally originating pathogenic species that can infiltrate and compromise the health of the animal. A sealed chamber also reduces the need for frequent chamber cleaning required to minimize the accumulation of pathogenic organisms. However, neurochemical measurements require specialized electrodes with extremely fragile carbon fiber tips and are not compatible with recently developed sealed chamber systems. Here, we leveraged osseointegrating materials and hermetic sealing strategies to enable both neurochemical and electrical neural activity measurements from a sealed chamber with an aspirating port for culturing chamber fluid to ensure an aseptic environment. The system was shown to provide successful recordings of neural activity in two monkeys while maintaining negative bacteria culture results for over a year post-implant.

Over the past decade, research has shown that the primary motor cortex (M1), the brain's main output for movement, also responds to rewards. These reward signals may shape motor output in its final stages, influencing movement invigoration and motor learning. In this Perspective, we highlight the functional roles of M1 reward signals and propose how they could guide advances in neurotechnologies for movement restoration, specifically brain-computer interfaces and non-invasive brain stimulation. Understanding M1 reward signals may open new avenues for enhancing motor control and rehabilitation.

Despite accounting for only ~0.001% of all neurons in the human brain, midbrain dopaminergic neurons control numerous behaviors and are associated with many neuropsychiatric disorders that affect our physical and mental health. Dopaminergic neurons form various anatomically and functionally segregated pathways. Having such defined dopaminergic pathways is key to controlling varied sets of brain functions; therefore, segregated dopaminergic pathways must be properly and uniquely formed during development. How are these segregated pathways established? The three key developmental stages that dopaminergic neurons go through are cell migration, axon guidance, and synapse formation. In each stage, dopaminergic neurons and their processes receive unique molecular cues to guide the formation of specific dopaminergic pathways. Here, we outline the molecular mechanisms underlying the establishment of segregated dopaminergic pathways during each developmental stage in the mouse brain, focusing on the formation of the three major dopaminergic pathways: the nigrostriatal, mesolimbic, and mesocortical pathways. We propose that multiple stage-specific molecular gradients cooperate to establish functionally segregated dopaminergic circuits.

Paired vagus nerve stimulation (VNS) has emerged as a promising strategy to potentiate recovery after neurological injury. This approach, which combines short bursts of electrical stimulation of the vagus nerve with rehabilitation exercises, received approval from the US Food and Drug Aministration in 2021 as the first neuromodulation-based therapy for chronic stroke. Because this treatment is increasingly implemented in clinical practice, there is a need to take stock of what we know about this approach and what we have yet to learn. Here, we provide a survey on the foundational basis of VNS therapy for stroke and offer insight into the mechanisms that underlie potentiated recovery, focusing on the principles of neuromodulatory reinforcement. We discuss the current state of observations regarding synaptic reorganization in motor networks that are enhanced by VNS, and we propose other prospective loci of neuromodulation that should be evaluated in the future. Finally, we highlight the future opportunities and challenges to be faced as this approach is increasingly translated to clinical use. Collectively, a clearer understanding of the mechanistic basis of VNS therapy may reveal ways to maximize its benefits.

The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens [NAc]). Notably, activation of the ERK (extracellular signal-regulated kinase) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control multiple forms of transcription-dependent neuroadaptations, but the dynamics and roles of striatal nuclear calcium signaling in preclinical models of addiction remain unknown.

A genetically encoded cell type-specific nuclear calcium probe has been developed to monitor calcium dynamics in the nuclei of striatal neurons, including in freely moving mice. A cell type-specific inhibitor of nuclear calcium signaling combined with 3-dimensional imaging of neuronal morphology, immunostaining, and behavior was used to disentangle the roles of nuclear calcium in NAc medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) or D2 receptor (D2R) on cocaine-evoked responses.

The D1R-mediated potentiation of calcium influx through glutamate NMDA receptors, which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice showed a sustained nuclear calcium increase in NAc D1R-MSNs. Disrupting nuclear calcium in D1R-MSNs, but not D2R-MSNs, blocked cocaine-evoked morphological changes of MSNs and gene expression and blunted cocaine's rewarding effects.

Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSNs on molecular, cellular, and behavioral adaptations to cocaine and represents a significant breakthrough because it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.

Mesolimbic dopamine (DA) neurons are central to sequence learning and habit formation. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution remain unknown. We designed two novel tasks to investigate how sequence initiation and termination cues influence DA-driven behavioral strategies and learning. We found that sequence initiation and termination cues differentially affect reward expectation during action sequences, with only the termination cue contributing to greater outcome devaluation insensitivity, automaticity and behavioral chunking. Mesolimbic fiber photometry recording revealed that this habit-like behavior was associated with a rapid backpropagation in DA signals from the reward to the immediately preceding cue and with attenuated DA reward prediction error signals, which reflected greater behavioral inflexibility. Finally, in absence of external cues, brief optogenetic stimulation of VTA DA neurons at sequence termination was sufficient to drive automaticity and behavioral chunking. Our results highlight the critical role of cue-evoked DA signals at sequence termination in mediating credit assignment and driving the development of habitual action sequence execution.

The temporal structure of sensory inputs contains essential information for their interpretation. Sensory cortex represents these temporal cues through two codes: the temporal sequences of neuronal activity and the spatial patterns of neuronal firing rate. However, it is unknown which of these coexisting codes causally drives sensory decisions. To separate their contributions, we generated in the mouse auditory cortex optogenetically driven activity patterns differing exclusively along their temporal or spatial dimensions. Mice could rapidly learn to behaviorally discriminate spatial but not temporal patterns. Moreover, large-scale neuronal recordings across the auditory system revealed that the auditory cortex is the first region in which spatial patterns efficiently represent temporal cues on the timescale of several hundred milliseconds. This feature is shared by the deep layers of neural networks categorizing time-varying sounds. Therefore, the emergence of a spatial code for temporal sensory cues is a necessary condition to efficiently associate temporally structured stimuli with decisions.

In the later stages of Parkinson's disease (PD), patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular and behavioral approaches. Our studies revealed that the intrinsic excitability and functional corticostriatal connectivity of SPNs in dyskinetic mice oscillate between the on- and off-states of LID in a cell- and state-specific manner. Although triggered by levodopa, these rapid oscillations in SPN properties depended on both dopaminergic and cholinergic signaling. In a mouse PD model, disrupting M1 muscarinic receptor signaling specifically in iSPNs or deleting its downstream signaling partner CalDAG-GEFI blunted the levodopa-induced oscillation in functional connectivity, enhanced the beneficial effects of levodopa and attenuated LID severity.

Dopaminergic neurotransmission plays a crucial role in motor function through the coordination of dopamine receptor (DRD) subtypes, such as DRD1 and DRD2, thus the functional imbalance of these receptors can lead to Parkinson's disease. However, due to the complexity of dopaminergic circuits in the brain, it is limited to investigating the individual functions of each DRD subtype in specific brain regions. Here, we developed a light-responsive chimeric DRD2, OptoDRD2, which can selectively activate DRD2-like signaling pathways with spatiotemporal resolution. OptoDRD2 was designed to include the light-sensitive component of rhodopsin and the intracellular signaling domain of DRD2. Upon illumination with blue light, OptoDRD2 triggered DRD2-like signaling pathways, such as Gαi/o subtype recruitment, a decrease in cAMP levels, and ERK phosphorylation. To explore unknown roles of DRD2 in glutamatergic cell populations of basal ganglia circuitry, OptoDRD2 was genetically expressed in excitatory neurons in lateral globus pallidus (LGP) of the male mouse brain. The optogenetic stimulation of OptoDRD2 in the LGP region affected a wide range of locomotion-related parameters, such as increased frequency of movement and decreased immobility time, resulting in the facilitation of motor function of living male mice. Therefore, our findings indicate a potentially novel role for DRD2 in the excitatory neurons of the LGP region, suggesting that OptoDRD2 can be a valuable tool enabling the investigation of unknown roles of DRD2 at specific cell types or brain regions.

Spatial memories guide navigation efficiently toward desired destinations. However, the neuronal and circuit mechanisms underlying the encoding of goal locations and its translation into goal-directed navigation remain unclear. Here we demonstrate that mice rapidly form a spatial memory of a shelter during shelter experiences, guiding escape behavior toward the goal location-a shelter-when under threat. Dopaminergic neurons in the ventral tegmental area and their projection to the nucleus accumbens (NAc) encode safety signals associated with the shelter. Optogenetically induced phasic dopamine signals are sufficient to create a place memory that directs escape navigation. Converging dopaminergic and hippocampal glutamatergic inputs to the NAc mediate the formation of a goal-related memory within a subpopulation of NAc neurons during shelter experiences. Artificial co-activation of this goal-related NAc ensemble with neurons in the dorsal periaqueductal gray was sufficient to trigger memory-guided, rather than random, escape behavior. These findings provide causal evidence of cognitive circuit modules linking memory with goal-directed action.

Dopamine signalling modes differ in kinetics and spatial patterns of receptor activation1,2. How these modes contribute to motor function, motivation and learning has long been debated3-21. Here we show that action-potential-induced dopamine release is dispensable for movement initiation but supports reward-oriented behaviour. We generated mice with dopamine-neuron-specific knockout of the release site organizer protein RIM to disrupt action-potential-induced dopamine release. In these mice, rapid in vivo dopamine dynamics were strongly impaired, but baseline dopamine persisted and fully supported spontaneous movement. Conversely, reserpine-mediated dopamine depletion or blockade of dopamine receptors disrupted movement initiation. The dopamine precursor L-DOPA reversed reserpine-induced bradykinesia without restoring fast dopamine dynamics, a result that substantiated the conclusion that these dynamics are dispensable for movement initiation. In contrast to spontaneous movement, reward-oriented behaviour was impaired in dopamine-neuron-specific RIM knockout mice. In conditioned place preference and two-odour discrimination tasks, the mice effectively learned to distinguish the cues, which indicates that reward-based learning persists after RIM ablation. However, the performance vigour was reduced. During probabilistic cue-reward association, dopamine dynamics and conditioned responses assessed through anticipatory licking were disrupted. These results demonstrate that action-potential-induced dopamine release is dispensable for motor function and subsecond precision of movement initiation but promotes motivation and performance during reward-guided behaviours.

Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients.

We recorded dopamine release signals in centromedial and centrolateral sectors of the striatum as mice learned consecutive versions of visual cue-outcome conditioning tasks. Dopamine release responses differed for the centromedial and centrolateral sites. In neither sector could these be accounted for by classic reinforcement learning alone as classically applied to the activity of nigral dopamine-containing neurons. Medially, cue responses ranged from initial sharp peaks to modulated plateau responses; outcome (reward) responses during cue conditioning were minimal or, initially, negative. At centrolateral sites, by contrast, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. At most sites, we found no evidence for a transition from outcome signaling to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopaminergic neuronal activity. These findings delineate a reshaping of striatal dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum.

The entorhinal cortex (EC) is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The EC thus has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. We found that dopamine neurons projecting their axons to the lateral EC (LEC), critical for memory formation in healthy brains, become dysfunctional and cause memory impairments in early AD brains. In amyloid precursor protein knock-in mice with associative memory impairment, LEC dopamine activity and associative memory encoding of LEC layer 2/3 neurons were disrupted in parallel from the early pathological stage. Optogenetic reactivation of LEC dopamine fibers, as well as L- DOPA treatment, rescued associative learning behavior. These results suggest that dysfunction of LEC-projecting dopamine neurons underlies memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in AD patients.

Striatal acetylcholine and dopamine critically regulate movement, motivation, and reward-related learning. Pauses in cholinergic interneuron (CIN) firing are thought to coincide with dopamine pulses encoding reward prediction errors (RPE) to jointly enable synaptic plasticity. Here, we examine the firing of identified CINs during reward-guided decision-making in freely moving rats and compare this firing to dopamine release. Relationships between CINs, dopamine, and behavior varied strongly by subregion. In the dorsal-lateral striatum, a Go! cue evoked burst-pause CIN spiking, followed by a brief dopamine pulse that was unrelated to RPE. In the dorsal-medial striatum, this cue evoked only a CIN pause, that was curtailed by a movement-selective rebound in firing. Finally, in the ventral striatum, a reward cue evoked RPE-coding increases in both dopamine and CIN firing, without a consistent pause. Our results demonstrate a spatial and temporal dissociation between CIN pauses and dopamine RPE signals and will inform future models of striatal information processing under both normal and pathological conditions.

Various mathematical models have been formulated to describe the changes in synaptic strengths resulting from spike-timing-dependent plasticity (STDP). A subset of these models include a third factor, dopamine, which interacts with spike timing to contribute to plasticity at specific synapses, notably those from cortex to striatum at the input layer of the basal ganglia. Theoretical work to analyze these plasticity models has largely focused on abstract issues, such as the conditions under which they may promote synchronization and the weight distributions induced by inputs with simple correlation structures, rather than on scenarios associated with specific tasks, and has generally not considered dopamine-dependent forms of STDP. In this paper we introduce three forms of dopamine-modulated STDP adapted from previously proposed plasticity rules. We then analyze, mathematically and with simulations, their performance in three biologically relevant scenarios. We test the ability of each of the three models to maintain its weights in the face of noise and to complete simple reward prediction and action selection tasks, studying the learned weight distributions and corresponding task performance in each setting. Interestingly, we find that each plasticity rule is well suited to a subset of the scenarios studied but falls short in others. Different tasks may therefore require different forms of synaptic plasticity, yielding the prediction that the precise form of the STDP mechanism present may vary across regions of the striatum, and other brain areas impacted by dopamine, that are involved in distinct computational functions.

Dopaminergic neurons play a crucial role in associative learning, but their capacity to regulate behavior on subsecond timescales remains debated. It is thought that dopaminergic neurons drive certain behaviors by rapidly modulating striatal spiking activity; however, a view has emerged that only artificially high (that is, supra-physiological) dopamine signals alter behavior on fast timescales. This raises the possibility that moment-to-moment striatal spiking activity is not strongly shaped by dopamine signals in the physiological range. To test this, we transiently altered dopamine levels while monitoring spiking responses in the ventral striatum of behaving mice. These manipulations led to only weak changes in striatal activity, except when dopamine release exceeded reward-matched levels. These findings suggest that dopaminergic neurons normally play a minor role in the subsecond modulation of striatal dynamics in relation to other inputs and demonstrate the importance of discerning dopaminergic neuron contributions to brain function under physiological and potentially nonphysiological conditions.

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal.

JOURNAL/nrgr/04.03/01300535-202410000-00028/figure1/v/2024-02-06T055622Z/r/image-tiff Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome. 3'-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3'-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3'-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3'-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3'-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3'-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3'-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3'-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.

The synaptic and neuronal circuit mechanisms underlying reward-based learning remain to be fully determined. In the mammalian brain, dopamine release in nucleus accumbens is thought to contribute importantly to reward signals for learning and promoting synaptic plasticity. Here, through longitudinal fiber photometry of a genetically-encoded fluorescent sensor, we investigated dopamine signals in the nucleus accumbens of thirsty head-restrained mice as they learned to lick a liquid reward spout in response to single deflections of the C2 whisker across varying reward contingencies. Reward delivery triggered by well-timed licking drove fast transient dopamine increases in nucleus accumbens. On the other hand, unrewarded licking was overall associated with reduced dopamine sensor fluorescence, especially in trials where reward was unexpectedly omitted. The dopamine reward signal upon liquid delivery decreased within individual sessions as mice became sated. As mice learned to lick the reward spout in response to whisker deflection, a fast transient sensory-evoked dopamine signal developed, correlating with the learning of the whisker detection task across consecutive training days, as well as within single learning sessions. The well-defined behavioral paradigm involving a unitary stimulus of a single whisker as a reward-predicting cue along with precisely quantified licking allows untangling of sensory, motor and reward-related dopamine signals and how they evolve across the learning of whisker-dependent goal-directed sensorimotor transformations. Our longitudinal measurements of dopamine dynamics across reward-based learning are overall consistent with the hypothesis that dopamine could play an important role as a reward signal for reinforcement learning.

We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown.

To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted.

In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling.

Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

One key function of the brain is to control our body's movements, allowing us to interact with the world around us. Yet, many motor behaviors are not innate but require learning through repeated practice. Among the brain's motor regions, the cortico-basal ganglia circuit is particularly crucial for acquiring and executing motor skills, and neuronal activity in these regions is directly linked to movement parameters. Cell-type-specific adaptations of activity patterns and synaptic connectivity support the learning of new motor skills. Functionally, neuronal activity sequences become structured and associated with learned movements. On the synaptic level, specific connections become potentiated during learning through mechanisms such as long-term synaptic plasticity and dendritic spine dynamics, which are thought to mediate functional circuit plasticity. These synaptic and circuit adaptations within the cortico-basal ganglia circuitry are thus critical for motor skill acquisition, and disruptions in this plasticity can contribute to movement disorders.

Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell-type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons, or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain.

Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), act as key regulators of neuronal development, survival, and plasticity. BDNF is necessary for neuronal and functional maintenance in the striatum and the substantia nigra, both structures involved in the pathogenesis of Parkinson's Disease (PD). Depletion of BDNF leads to striatal degeneration and defects in the dendritic arborization of striatal neurons. Activation of tropomyosin receptor kinase B (TrkB) by BDNF is necessary for the induction of long-term potentiation (LTP), a form of synaptic plasticity, in the hippocampus and striatum. PD is characterized by the degeneration of nigrostriatal neurons and altered striatal plasticity has been implicated in the pathophysiology of PD motor symptoms, leading to imbalances in the basal ganglia motor pathways. Given its essential role in promoting neuronal survival and meditating synaptic plasticity in the motor system, BDNF might have an important impact on the pathophysiology of neurodegenerative diseases, such as PD. In this review, we focus on the role of BDNF in corticostriatal plasticity in movement disorders, including PD and dystonia. We discuss the mechanisms of how dopaminergic input modulates BDNF/TrkB signaling at corticostriatal synapses and the involvement of these mechanisms in neuronal function and synaptic plasticity. Evidence for alterations of BDNF and TrkB in PD patients and animal models are reviewed, and the potential of BDNF to act as a therapeutic agent is highlighted. Advancing our understanding of these mechanisms could pave the way toward innovative therapeutic strategies aiming at restoring neuroplasticity and enhancing motor function in these diseases.

Decision-making under risk is a common challenge. It is known that risk-taking behavior varies between contexts of reward and punishment, yet the mechanisms underlying this asymmetry in risk sensitivity remain unclear.

This study used a monetary task to investigate neurochemical mechanisms and brain dynamics underpinning risk sensitivity. Twenty-eight participants engaged in a task requiring selection of visual stimuli to maximize monetary gains and minimize monetary losses. We modeled participant trial-and-error processes using reinforcement learning.

Participants with higher subjective utility parameters showed risk preference in the gain domain (r = -0.59) and risk avoidance in the loss domain (r = -0.77). Magnetic resonance spectroscopy (MRS) revealed that risk avoidance in the loss domain was associated with γ-aminobutyric acid (GABA) levels in the ventral striatum (r = -0.42), but not in the insula (r = -0.15). Using functional magnetic resonance imaging (fMRI), we tested whether risk-sensitive brain dynamics contribute to participant risky choices. Energy landscape analyses demonstrated that higher switching rates between brain states, including the striatum and insula, were correlated with risk avoidance in the loss domain (r = -0.59), a relationship not observed in the gain domain (r = -0.02).

These findings from MRS and fMRI suggest that distinct mechanisms are involved in gain/loss decision making, mediated by subcortical neurometabolite levels and brain dynamic transitions.