Adaptation of sequential action benefits from timing variability related to lateral basal ganglia circuitry.

Streamlined action sequences must remain flexible should stable contingencies in the environment change. By combining analyses of behavioral structure with a circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relates to post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). In a two-lever instrumental task, mice formed successful action sequences by, first, establishing action scaffolds and, second, smoothly extending action duration to adapt to increased task requirements.

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain.

Restoring the youthful state of striatal plasticity in aged mice re-enables cognitive control of action.

Multidisciplinary evidence suggests that the control of voluntary action arbitrates between two major forms of behavioral processing: cognitively guided (or goal directed) and autonomously guided (or habitual). Brain-state irregularities affecting the striatum-such as aging-commonly shift control toward the latter, although the responsible neural mechanisms remain unknown. Combining instrumental conditioning with cell-specific mapping and chemogenetics in striatal neurons, we explored strategies that invigorate goal-directed capacity in aged mice.

Single Dose of Amphetamine Induces Delayed Subregional Attenuation of Cholinergic Interneuron Activity in the Striatum.

Psychostimulants such as amphetamine (AMPH) target dopamine (DA) neuron synapses to engender drug-induced plasticity. While DA neurons modulate the activity of striatal (Str) cholinergic interneurons (ChIs) with regional heterogeneity, how AMPH affects ChI activity has not been elucidated. Here, we applied quantitative fluorescence imaging approaches to map the dose-dependent effects of a single dose of AMPH on ChI activity at 2.

Amygdala-Cortical Control of Striatal Plasticity Drives the Acquisition of Goal-Directed Action.

In mammalian species, the capacity for goal-directed action relies on a process of cognitive-emotional integration, which melds the causal and incentive learning processes that link action-goal associations with the current value of the goal [1]. Recent evidence suggests that such integration depends on a cortical-limbic-striatal circuit centered on the posterior dorsomedial striatum (pDMS) [2]. Learning-related plasticity has been described at both classes of principal neuron in the pDMS, the direct (dSPNs) and indirect (iSPNs) pathway spiny projection neurons [3-5], and is thought to depend on inputs from prelimbic cortex (PL) [6] and the basolateral amygdala (BLA) [7].

Basolateral Amygdala Drives a GPCR-Mediated Striatal Memory Necessary for Predictive Learning to Influence Choice.

Predictive learning exerts a powerful influence over choice between instrumental actions. Nevertheless, how this learning is encoded in a sufficiently stable manner to influence choices that can occur much later in time is unclear. Here, we report that the basolateral amygdala (BLA) encodes predictive learning and establishes the memory necessary for future choices by driving the accumulation of delta-opioid receptors (DOPRs) on the somatic membrane of cholinergic interneurons in the nucleus accumbens shell (NAc-S).

Local D2- to D1-neuron transmodulation updates goal-directed learning in the striatum.

Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits that mediate goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of spiny projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN transmodulation across the striatum that is necessary for updating previous goal-directed learning.

Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria.

Accumulation of the protein tau characterises Alzheimer's disease and other tauopathies, including familial forms of frontotemporal dementia (FTD) that carry pathogenic tau mutations. Another hallmark feature of these diseases is the accumulation of dysfunctional mitochondria. Although disease-associated tau is known to impair several aspects of mitochondrial function, it is still unclear whether it also directly impinges on mitochondrial quality control, specifically Parkin-dependent mitophagy.

The Thalamostriatal Pathway and the Hierarchical Control of Action.

Sequential ordering of motor commands is required for the simplest of our daily activities. In this issue of Neuron, Díaz-Hernández et al. (2018) show that distinct thalamic inputs to different regions of the dorsal striatum critically modulate the initiation and execution of action sequences.

A corticostriatal deficit promotes temporal distortion of automatic action in ageing.

The acquisition of motor skills involves implementing action sequences that increase task efficiency while reducing cognitive loads. This learning capacity depends on specific cortico-basal ganglia circuits that are affected by normal ageing. Here, combining a series of novel behavioural tasks with extensive neuronal mapping and targeted cell manipulations in mice, we explored how ageing of cortico-basal ganglia networks alters the microstructure of action throughout sequence learning.

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system.

Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs) have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood.

Aging-Related Dysfunction of Striatal Cholinergic Interneurons Produces Conflict in Action Selection.

For goal-directed action to remain adaptive, new strategies are required to accommodate environmental changes, a process for which parafascicular thalamic modulation of cholinergic interneurons in the striatum (PF-to-CIN) appears critical. In the elderly, however, previously acquired experience frequently interferes with new learning, yet the source of this effect has remained unexplored. Here, combining sophisticated behavioral designs, cell-specific manipulation, and extensive neuronal imaging, we investigated the involvement of the PF-to-CIN pathway in this process.

δ-opioid and dopaminergic processes in accumbens shell modulate the cholinergic control of predictive learning and choice.

Decision-making depends on the ability to extract predictive information from the environment to guide future actions. Outcome-specific Pavlovian-instrumental transfer (PIT) provides an animal model of this process in which a stimulus predicting a particular outcome biases choice toward actions earning that outcome. Recent evidence suggests that cellular adaptations of δ-opioid receptors (DORs) on cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) are necessary for PIT.

Learning-related translocation of δ-opioid receptors on ventral striatal cholinergic interneurons mediates choice between goal-directed actions.

The ability of animals to extract predictive information from the environment to inform their future actions is a critical component of decision-making. This phenomenon is studied in the laboratory using the pavlovian-instrumental transfer protocol in which a stimulus predicting a specific pavlovian outcome biases choice toward those actions earning the predicted outcome. It is well established that this transfer effect is mediated by corticolimbic afferents on the nucleus accumbens shell (NAc-S), and recent evidence suggests that δ-opioid receptors (DORs) play an essential role in this effect.

The thalamostriatal pathway and cholinergic control of goal-directed action: interlacing new with existing learning in the striatum.

The capacity for goal-directed action depends on encoding specific action-outcome associations, a learning process mediated by the posterior dorsomedial striatum (pDMS). In a changing environment, plasticity has to remain flexible, requiring interference between new and existing learning to be minimized, yet it is not known how new and existing learning are interlaced in this way. Here we investigated the role of the thalamostriatal pathway linking the parafascicular thalamus (Pf) with cholinergic interneurons (CINs) in the pDMS in this process.

Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1.

The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. We found that administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which preferentially express dopamine D2 receptors (D2Rs).

Striatal cholinergic interneurons display activity-related phosphorylation of ribosomal protein S6.

Cholinergic interneurons (CINs) provide the main source of acetylcholine to all striatal regions, and strongly modulate dopaminergic actions through complex regulation of pre- and post-synaptic acetylcholine receptors. Although striatal CINs have a well-defined electrophysiological profile, their biochemical properties are poorly understood, likely due to their low proportion within the striatum (2-3%). We report a strong and sustained phosphorylation of ribosomal protein S6 on its serine 240 and 244 residues (p-Ser²⁴⁰⁻²⁴⁴-S6rp), a protein integrant of the ribosomal machinery related to the mammalian target of the rapamycin complex 1 (mTORC1) pathway, which we found to be principally expressed in striatal CINs in basal conditions.

Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32.

Administration of typical antipsychotic drugs, such as haloperidol, promotes cAMP-dependent signaling in the medium spiny neurons (MSNs) of the striatum. In this study, we have examined the effect of haloperidol on the state of phosphorylation of the ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. We found that haloperidol increases the phosphorylation of rpS6 at the dual site Ser235/236, which is involved in the regulation of mRNA translation.

What is the Degree of Segregation between Striatonigral and Striatopallidal Projections?

In contrast to most other brain regions, in the striatum the output neurons (the medium-sized spiny neurons, MSNs) are GABAergic and act by inhibiting their targets. The standard model of the basal ganglia is built on the segregation of information processing in the direct and indirect pathways, which act in opposing directions to control movement. The MSNs participating in these two pathways can be identified according to their projection sites and the proteins they express.

Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice.

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT(2B) receptor-dependent.

Looking BAC at striatal signaling: cell-specific analysis in new transgenic mice.

Understanding how molecular signaling pathways participate in behavioral responses requires determining precisely in which neuronal populations they are activated. The recent development of bacterial artificial chromosome (BAC) transgenic mice expressing a variety of reporters, epitope tagged-proteins or Cre recombinase driven by specific promoters, is a significant step forward in this direction. These mice help overcome the limitations of traditional approaches that examine an average of signaling events occurring in mixed populations of cells.

Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol.

A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, as well as neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, sensitization mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization showed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS).

Striatal medium-sized spiny neurons: identification by nuclear staining and study of neuronal subpopulations in BAC transgenic mice.

Precise identification of neuronal populations is a major challenge in neuroscience. In the striatum, more than 95% of neurons are GABAergic medium-sized spiny neurons (MSNs), which form two intermingled populations distinguished by their projections and protein content. Those expressing dopamine D(1)-receptors (D1Rs) project preferentially to the substantia nigra pars reticulata (SNr), whereas those expressing dopamine D(2)- receptors (D2Rs) project preferentially to the lateral part of the globus pallidus (LGP).