The striatum is required for the acquisition of procedural memories, but its contribution to motor control once learning has occurred is unclear. We created a task in which rats learned a difficult ...motor sequence characterized by fine-tuned changes in running speed adjusted to spatial and temporal constraints. After training and extensive practice, we found that the behavior was habitual, yet tetrode recordings in the dorsolateral striatum (DLS) revealed continuous integrative representations of running speed, position and time. These representations were weak in naive rats that were hand-guided to perform the same sequence and developed slowly after learning. Finally, DLS inactivation in well-trained animals preserved the structure of the sequence while increasing its trial-by-trial variability. We conclude that, after learning, the DLS continuously integrates task-relevant information to constrain the execution of motor habits. Our results provide a straightforward mechanism by which the basal ganglia may contribute to habit formation and motor control.
This study investigated the neuroprotective effects of resveratrol (RVT)-loaded polysorbate 80 (PS80)-coated poly(lactide) nanoparticles in a mouse model of Parkinson's disease (PD), and compared ...these effects with those from bulk RVT.
C57BL/6 mice received for 15 days RVT intraperitoneally (nanoparticulate or non-nanoparticulate), as well as single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that damages dopaminergic neurons and induces PD-related symptoms.
MPTP induced significant impairments on olfactory discrimination and social recognition memory, as well as caused striatal oxidative stress and reduced the expression of tyrosine hydroxylase in striatum. RVT-loaded nanoparticles (but not bulk) displayed significant neuroprotection against MPTP-induced behavioral and neurochemical changes.
These results point to RVT-loaded poly(lactide)-nanoparticles coated with PS80 a promising nanomedical tool and adjuvant therapy for PD.
•Treatment of rotenone-exposed rats with kolaviron conferred neuroprotection.•Kolaviron mitigated ROT-induced neuromuscular incompetence and exploratory deficits.•Kolaviron improved capacity to ...maintain efficient gait and coordination with minimal rigidity.•Kolaviron prevented striatal neurodegeneration, neurobiochemical imbalance and neuroinflammation.•Kolaviron treatment was more potent in preventing progressive neurodegeneration.
Parkinson’s disease is the most prevalent movement disorder. Currently, therapies are palliative with associated irreversible behavioural incompetence. Here, we investigated the ability of kolaviron (KV), an anti-inflammatory biflavonoid isolated form Garcinia kola seeds, to rescue striatal neuronal damage and redo-inflammation in rats exposed to rotenone (ROT). Aged rats exposed to 11 days of rotenone intoxication were treated with KV either concurrently or for 18 days. The 18-day regimen included 7 days of pre-treatment prior 11-day concurrent ROT-KV treatment.
Rotenone-exposed rats lost weight appreciably and travelled less distance with reduced speed, decline efficiency to maintain a straight path, enhanced freezing, increased immobile episodes and poor hole recognition. The motor incompetence was attributed to enhanced striatal neurodegeneration, increased alpha synuclein formation and reduced tyrosine hydroxylase expression. ROT intoxication significantly increased reactive species production, which co-existed with induction of striatal antioxidant system and damage to biomolecules. ROT additionally upregulated COX-2 expression, enhanced myeloperoxidase activity and increased concentration of striatal inteleukine-6 (IL-6), IL-1β and tumour necrosis factor (TNF-α). Treatment with kolaviron reversed the rotenone-associated locomotor impairment and exploratory deficits, motor/neuromuscular incompetence, striatal neurodegeneration, neurobiochemical imbalance, altered antioxidant defence system and neuroinflammation. KV-treated rats showed improved capacity to maintain efficient gait with minimal rigidity and enhanced coordination.
Taken together, kolaviron exhibited neuroprotective properties, which may be beneficial for the prevention and management of Parkinson’s disease, via antioxidant, anti-inflammatory and anti-apoptotic mechanisms.
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. Removing the excitatory input from Pf to the CINs was found to reduce the firing rate and intrinsic activity of these neurons and produced an enduring deficit in goal-directed learning after changes in the action-outcome contingency. Disconnection of the Pf-pDMS pathway produced similar behavioral effects. These data suggest that CINs reduce interference between new and existing learning, consistent with claims that the thalamostriatal pathway exerts state control over learning-related plasticity.
•The thalamostriatal pathway modulates activity in striatal cholinergic interneurons•Altering striatal cholinergic activity does not affect initial goal-directed learning•Striatal cholinergic activity is critical for new learning after contingencies change•The thalamostriatal pathway reduces interference between new and existing learning
The thalamostriatal pathway controls cholinergic activity in the dorsomedial striatum, an area that is critical for learning new goal-directed actions. Here Bradfield et al. show that striatal cholinergic activity is necessary to interlace new with existing learning when acquiring new actions.
Although the human amygdala and striatum have both been implicated in associative learning, only the striatum's contribution has been consistently computationally characterized. Using a reversal ...learning task, we found that amygdala blood oxygen level-dependent activity tracked associability as estimated by a computational model, and dissociated it from the striatal representation of reinforcement prediction error. These results extend the computational learning approach from striatum to amygdala, demonstrating their complementary roles in aversive learning.
Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual's health and ...social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.
Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated ...with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, (18)FDPA-714 N,N-diethyl-2-(2-(4-(2-(18)Ffluoroethoxy)phenyl)-5,7-dimethylpyrazolo1,5-apyrimidin-3-yl)acetamide and (11)CSSR180575 (7-chloro-N,N-dimethyl-5-(11)Cmethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino4,5-bindole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.
Striatal cholinergic interneurons (ChIs) are central for the processing and reinforcement of reward‐related behaviors that are negatively affected in states of altered dopamine transmission, such as ...in Parkinson's disease or drug addiction. Nevertheless, the development of therapeutic interventions directed at ChIs has been hampered by our limited knowledge of the diverse anatomical and functional characteristics of these neurons in the dorsal and ventral striatum, combined with the lack of pharmacological tools to modulate specific cholinergic receptor subtypes. This review highlights some of the key morphological, synaptic, and functional differences between ChIs of different striatal regions and across species. It also provides an overview of our current knowledge of the cellular localization and function of cholinergic receptor subtypes. The future use of high‐resolution anatomical and functional tools to study the synaptic microcircuitry of brain networks, along with the development of specific cholinergic receptor drugs, should help further elucidate the role of striatal ChIs and permit efficient targeting of cholinergic systems in various brain disorders, including Parkinson's disease and addiction.
The development of the striatum dopamine (DA) system through human adolescence, a time of increased sensation seeking and vulnerability to the emergence of psychopathology, has been difficult to ...study due to pediatric restrictions on direct in vivo assessments of DA. Here, we applied neuroimaging in a longitudinal sample of n = 146 participants aged 12-30. R2', an MR measure of tissue iron which co-localizes with DA vesicles and is necessary for DA synthesis, was assessed across the sample. In the 18-30 year-olds (n = 79) we also performed PET using 11Cdihydrotetrabenazine (DTBZ), a measure of presynaptic vesicular DA storage, and 11Craclopride (RAC), an indicator of D2/D3 receptor availability. We observed decreases in D2/D3 receptor availability with age, while presynaptic vesicular DA storage (as measured by DTBZ), which was significantly associated with R2' (standardized coefficient = 0.29, 95% CI = 0.11, 0.48), was developmentally stable by age 18. Our results provide new evidence for maturational specialization of the striatal DA system through adolescence.
Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. ...Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using (18)Ffallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.
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