Anti-Hebbian plasticity drives sequence learning in striatum.

Spatio-temporal activity patterns have been observed in a variety of brain areas in spontaneous activity, prior to or during action, or in response to stimuli. Biological mechanisms endowing neurons with the ability to distinguish between different sequences remain largely unknown. Learning sequences of spikes raises multiple challenges, such as maintaining in memory spike history and discriminating partially overlapping sequences. Here, we show that anti-Hebbian spike-timing dependent plasticity (STDP), as observed at cortico-striatal synapses, can naturally lead to learning spike sequences. We design a spiking model of the striatal output neuron receiving spike patterns defined as sequential input from a fixed set of cortical neurons. We use a simple synaptic plasticity rule that combines anti-Hebbian STDP and non-associative potentiation for a subset of the presented patterns called rewarded patterns. We study the ability of striatal output neurons to discriminate rewarded from non-rewarded patterns by firing only after the presentation of a rewarded pattern. In particular, we show that two biological properties of striatal networks, spiking latency and collateral inhibition, contribute to an increase in accuracy, by allowing a better discrimination of partially overlapping sequences. These results suggest that anti-Hebbian STDP may serve as a biological substrate for learning sequences of spikes.

Information flow between motor cortex and striatum reverses during skill learning.

The coordination of neural activity across brain areas during a specific behavior is often interpreted as neural communication involved in controlling the behavior. However, whether information relevant to the behavior is actually transferred between areas is often untested. Here, we used information-theoretic tools to quantify how motor cortex and striatum encode and exchange behaviorally relevant information about specific reach-to-grasp movement features during skill learning in rats. We found a temporal shift in the encoding of behaviorally relevant information during skill learning, as well as a reversal in the primary direction of behaviorally relevant information flow, from cortex-to-striatum during naive movements to striatum-to-cortex during skilled movements. Standard analytical methods that quantify the evolution of overall neural activity during learning-such as changes in neural signal amplitude or the overall exchange of information between areas-failed to capture these behaviorally relevant information dynamics. Using these standard methods, we instead found a consistent coactivation of overall neural signals during movement production and a bidirectional increase in overall information propagation between areas during learning. Our results show that skill learning is achieved through a transformation in how behaviorally relevant information is routed across cortical and subcortical brain areas and that isolating the components of neural activity relevant to and informative about behavior is critical to uncover directional interactions within a coactive and coordinated network.

Dopamine lesions alter the striatal encoding of single-limb gait.

The striatum serves an important role in motor control, and neurons in this area encode the body's initiation, cessation, and speed of locomotion. However, it remains unclear whether the same neurons also encode the step-by-step rhythmic motor patterns of individual limbs that characterize gait. By combining high-speed video tracking, electrophysiology, and optogenetic tagging, we found that a sizable population of both D1 and D2 receptor expressing medium spiny projection neurons (MSNs) were phase-locked to the gait cycle of individual limbs in mice. Healthy animals showed balanced limb phase-locking between D1 and D2 MSNs, while dopamine depletion led to stronger phase-locking in D2 MSNs. These findings indicate that striatal neurons represent gait on a single-limb and step basis, and suggest that elevated limb phase-locking of D2 MSNs may underlie some of the gait impairments associated with dopamine loss.

Neural inhibition as implemented by an actor-critic model involves the human dorsal striatum and ventral tegmental area.

Inhibition is implicated across virtually all human experiences. As a trade-off of being very efficient, this executive function is also prone to many errors. Rodent and computational studies show that midbrain regions play crucial roles during errors by sending dopaminergic learning signals to the basal ganglia for behavioural adjustment. However, the parallels between animal and human neural anatomy and function are not determined. We scanned human adults while they performed an fMRI inhibitory task requiring trial-and-error learning. Guided by an actor-critic model, our results implicate the dorsal striatum and the ventral tegmental area as the actor and the critic, respectively. Using a multilevel and dimensional approach, we also demonstrate a link between midbrain and striatum circuit activity, inhibitory performance, and self-reported autistic and obsessive-compulsive subclinical traits.

Distinct neurochemical influences on fMRI response polarity in the striatum.

The striatum, known as the input nucleus of the basal ganglia, is extensively studied for its diverse behavioral roles. However, the relationship between its neuronal and vascular activity, vital for interpreting functional magnetic resonance imaging (fMRI) signals, has not received comprehensive examination within the striatum. Here, we demonstrate that optogenetic stimulation of dorsal striatal neurons or their afferents from various cortical and subcortical regions induces negative striatal fMRI responses in rats, manifesting as vasoconstriction. These responses occur even with heightened striatal neuronal activity, confirmed by electrophysiology and fiber-photometry. In parallel, midbrain dopaminergic neuron optogenetic modulation, coupled with electrochemical measurements, establishes a link between striatal vasodilation and dopamine release. Intriguingly, in vivo intra-striatal pharmacological manipulations during optogenetic stimulation highlight a critical role of opioidergic signaling in generating striatal vasoconstriction. This observation is substantiated by detecting striatal vasoconstriction in brain slices after synthetic opioid application. In humans, manipulations aimed at increasing striatal neuronal activity likewise elicit negative striatal fMRI responses. Our results emphasize the necessity of considering vasoactive neurotransmission alongside neuronal activity when interpreting fMRI signal.

Crym-positive striatal astrocytes gate perseverative behaviour.

Astrocytes are heterogeneous glial cells of the central nervous system1-3. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses µ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders4-7. In adult mice, reducing the levels of µ-crystallin in striatal astrocytes through CRISPR-Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory-inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics8, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders9-12. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration.

Corticostriatal activity related to performance during continuous de novo motor learning.

Corticostriatal regions play a pivotal role in visuomotor learning. However, less research has been done on how fMRI activity in their subregions is related to task performance, which is provided as visual feedback during motor learning. To address this, we conducted an fMRI experiment in which participants acquired a complex de novo motor skill using continuous or binary visual feedback related to performance. We found a highly selective response related to performance in the entire striatum in both conditions and a relatively higher response in the caudate nucleus for the binary feedback condition. However, the ventromedial prefrontal cortex (vmPFC) response was significant only for the continuous feedback condition. Furthermore, we also found functional distinction of the striatal subregions in random versus goal-directed motor control. These findings underscore the substantial effects of the visual feedback indicating performance on distinct corticostriatal responses, thereby elucidating its significance in reinforcement-based motor learning.

Local regulation of striatal dopamine: A diversity of circuit mechanisms for a diversity of behavioral functions?

Striatal dopamine governs a wide range of behavioral functions, yet local dopamine concentrations can be dissociated from somatic activity. Here, we discuss how dopamine's diverse roles in behavior may be driven by local circuit mechanisms shaping dopamine release. We first look at historical and recent work demonstrating that striatal circuits interact with dopaminergic terminals to either initiate the release of dopamine or modulate the release of dopamine initiated by spiking in midbrain dopamine neurons, with particular attention to GABAergic and cholinergic local circuit mechanisms. Then we discuss some of the first in vivo studies of acetylcholine-dopamine interactions in striatum and broadly discuss necessary future work in understanding the roles of midbrain versus striatal dopamine regulation.

Striatal and Behavioral Responses to Reward Vary by Socioeconomic Status in Adolescents.

Disparities in socioeconomic status (SES) lead to unequal access to financial and social support. These disparities are believed to influence reward sensitivity, which in turn are hypothesized to shape how individuals respond to and pursue rewarding experiences. However, surprisingly little is known about how SES shapes reward sensitivity in adolescence. Here, we investigated how SES influenced adolescent responses to reward, both in behavior and the striatum-a brain region that is highly sensitive to reward. We examined responses to both immediate reward (tracked by phasic dopamine) and average reward rate fluctuations (tracked by tonic dopamine) as these distinct signals independently shape learning and motivation. Adolescents (n = 114; 12-14 years; 58 female) performed a gambling task during functional magnetic resonance imaging. We manipulated trial-by-trial reward and loss outcomes, leading to fluctuations between periods of reward scarcity and abundance. We found that a higher reward rate hastened behavioral responses, and increased guess switching, consistent with the idea that reward abundance increases response vigor and exploration. Moreover, immediate reward reinforced previously rewarding decisions (win-stay, lose-switch) and slowed responses (postreward pausing), particularly when rewards were scarce. Notably, lower-SES adolescents slowed down less after rare rewards than higher-SES adolescents. In the brain, striatal activations covaried with the average reward rate across time and showed greater activations during rewarding blocks. However, these striatal effects were diminished in lower-SES adolescents. These findings show that the striatum tracks reward rate fluctuations, which shape decisions and motivation. Moreover, lower SES appears to attenuate reward-driven behavioral and brain responses.

Prefrontal signals precede striatal signals for biased credit assignment in motivational learning biases.

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear. Specifically, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and control beyond stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dorsal anterior and posterior cingulate cortices) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.

Striatal Neurons Are Recruited Dynamically into Collective Representations of Self-Initiated and Learned Actions in Freely Moving Mice.

Striatal spiny projection neurons are hyperpolarized-at-rest (HaR) and driven to action potential threshold by a small number of powerful inputs-an input-output configuration that is detrimental to response reliability. Because the striatum is important for habitual behaviors and goal-directed learning, we conducted a microendoscopic imaging in freely moving mice that express a genetically encoded Ca2+ indicator sparsely in striatal HaR neurons to evaluate their response reliability during self-initiated movements and operant conditioning. The sparse expression was critical for longitudinal studies of response reliability, and for studying correlations among HaR neurons while minimizing spurious correlations arising from contamination by the background signal. We found that HaR neurons are recruited dynamically into action representation, with distinct neuronal subsets being engaged in a moment-by-moment fashion. While individual neurons respond with little reliability, the population response remained stable across days. Moreover, we found evidence for the temporal coupling between neuronal subsets during conditioned (but not innate) behaviors.

GABAergic regulation of striatal spiny projection neurons depends upon their activity state.

Synaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at subthreshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical, and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. In perforated patch recordings, activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in both juvenile and adult SPNs. Transcriptomic analysis and pharmacological work suggested that this relatively positive GABAAR reversal potential was not attributable to NKCC1 expression, but rather to HCO3- permeability. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to dendritic iGluR signaling and promoted dendritic spikes. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation for the role of intrastriatal GABAergic circuits.

Effective Regulation of Auditory Processing by Parvalbumin Interneurons in the Tail of the Striatum.

Parvalbumin (PV) interneurons in the auditory cortex (AC) play a crucial role in shaping auditory processing, including receptive field formation, temporal precision enhancement, and gain regulation. PV interneurons are also the primary inhibitory neurons in the tail of the striatum (TS), which is one of the major descending brain regions in the auditory nervous system. However, the specific roles of TS-PV interneurons in auditory processing remain elusive. In this study, morphological and slice recording experiments in both male and female mice revealed that TS-PV interneurons, compared with AC-PV interneurons, were present in fewer numbers but exhibited longer projection distances, which enabled them to provide sufficient inhibitory inputs to spiny projection neurons (SPNs). Furthermore, TS-PV interneurons received dense auditory input from both the AC and medial geniculate body (MGB), particularly from the MGB, which rendered their auditory responses comparable to those of AC-PV interneurons. Optogenetic manipulation experiments demonstrated that TS-PV interneurons were capable of bidirectionally regulating the auditory responses of SPNs. Our findings suggest that PV interneurons can effectively modulate auditory processing in the TS and may play a critical role in auditory-related behaviors.

Striatal dopamine integrates cost, benefit, and motivation.

Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these signals vary with motivation. Here, we measure DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) while independently varying costs and benefits and apply behavioral economic principles to determine a mouse's level of motivation. We reveal that DA release in both structures incorporates both reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release. Furthermore, optogenetically evoked DA release was also heavily dependent on sunk cost. Our results reconcile previous disparate findings by demonstrating that striatal DA release simultaneously encodes cost, benefit, and motivation but in distinct manners over different timescales. Future work will be necessary to determine whether the reduction in phasic DA release in highly motivated animals is due to changes in tonic DA levels.

Circuit mechanisms of navigation strategy learning in mice.

Navigation tasks involve the gradual selection and deployment of increasingly effective searching procedures to reach targets. The brain mechanisms underlying such complex behavior are poorly understood, but their elucidation might provide insights into the systems linking exploration and decision making in complex learning. Here, we developed a trial-by-trial goal-related search strategy analysis as mice learned to navigate identical water mazes encompassing distinct goal-related rules and monitored the strategy deployment process throughout learning. We found that navigation learning involved the following three distinct phases: an early phase during which maze-specific search strategies are deployed in a minority of trials, a second phase of preferential increasing deployment of one search strategy, and a final phase of increasing commitment to this strategy only. The three maze learning phases were affected differently by inhibition of retrosplenial cortex (RSC), dorsomedial striatum (DMS), or dorsolateral striatum (DLS). Through brain region-specific inactivation experiments and gain-of-function experiments involving activation of learning-related cFos+ ensembles, we unraveled how goal-related strategy selection relates to deployment throughout these sequential processes. We found that RSC is critically important for search strategy selection, DMS mediates strategy deployment, and DLS ensures searching consistency throughout maze learning. Notably, activation of specific learning-related ensembles was sufficient to direct strategy selection (RSC) or strategy deployment (DMS) in a different maze. Our results establish a goal-related search strategy deployment approach to dissect unsupervised navigation learning processes and suggest that effective searching in navigation involves evidence-based goal-related strategy direction by RSC, reinforcement-modulated strategy deployment through DMS, and online guidance through DLS.

Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning.

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here we show successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, functional magnetic resonance imaging studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as an exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional role. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.

Striatopallidal cannabinoid type-1 receptors mediate amphetamine-induced sensitization.

Repeated exposure to psychostimulants, such as amphetamine, causes a long-lasting enhancement in the behavioral responses to the drug, called behavioral sensitization.1 This phenomenon involves several neuronal systems and brain areas, among which the dorsal striatum plays a key role.2 The endocannabinoid system (ECS) has been proposed to participate in this effect, but the neuronal basis of this interaction has not been investigated.3 In the CNS, the ECS exerts its functions mainly acting through the cannabinoid type-1 (CB1) receptor, which is highly expressed at terminals of striatal medium spiny neurons (MSNs) belonging to both the direct and indirect pathways.4 In this study, we show that, although striatal CB1 receptors are not involved in the acute response to amphetamine, the behavioral sensitization and related synaptic changes require the activation of CB1 receptors specifically located at striatopallidal MSNs (indirect pathway). These results highlight a new mechanism of psychostimulant sensitization, a phenomenon that plays a key role in the health-threatening effects of these drugs.

The basal ganglia are a target for sensorimotor domains in posterior parietal, premotor, and motor cortex in primates.

Our research focused on defining and characterizing parieto-frontal circuits for specific actions in primates. Part of the posterior parietal cortex is divided into eight or more domains where electrical stimulation evokes a meaningful complex movement. Domains in the posterior parietal cortex compete with each other over excitatory connections that activate inhibitory neurons, while selectively activating functionally matched domains in the premotor cortex and motor cortex. Thus, the selection process involves competition and cooperation between domains over three different regions of cortex. In addition, projections from functionally matched domains in motor regions converge in the matrix of the striatum, whereas projections from different functionally unmatched domains are separate. Thus, the projections of action-specific domains include the basal ganglia, where actions can be permitted or blocked.

NECAB2 is an endosomal protein important for striatal function.

Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal function.

Dissociating the contributions of sensorimotor striatum to automatic and visually guided motor sequences.

The ability to sequence movements in response to new task demands enables rich and adaptive behavior. However, such flexibility is computationally costly and can result in halting performances. Practicing the same motor sequence repeatedly can render its execution precise, fast and effortless, that is, 'automatic'. The basal ganglia are thought to underlie both types of sequence execution, yet whether and how their contributions differ is unclear. We parse this in rats trained to perform the same motor sequence instructed by cues and in a self-initiated overtrained, or 'automatic,' condition. Neural recordings in the sensorimotor striatum revealed a kinematic code independent of the execution mode. Although lesions reduced the movement speed and affected detailed kinematics similarly, they disrupted high-level sequence structure for automatic, but not visually guided, behaviors. These results suggest that the basal ganglia are essential for 'automatic' motor skills that are defined in terms of continuous kinematics, but can be dispensable for discrete motor sequences guided by sensory cues.