Does compulsion explain addiction?

One of the leading drug addiction theories states that habits and the underlying neural process of a ventral to dorsal striatal shift are the building blocks of compulsive drug-seeking behaviour and that compulsion is the maladaptive persistence of responding despite adverse consequences. Here we discuss that compulsive behaviour as defined primarily from the perspective of animal experimentation falls short of the clinical phenomena and their neurobiological correlates. Thus for the human condition, the concept of compulsive habbits should be critically addressed and potentially revised.

Delayed levodopa-responsive parkinsonism following acute midbrain injury.

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Anterior cingulate cortex and insomnia: A cingulate-striatum connection.

Insomnia is an important comorbidity of chronic pain. In this issue of Neuron, Li et al. report that chronic-pain-induced insomnia is mediated by the pyramidal neurons in the anterior cingulate cortex and their dopaminergic projections to the dorsal medial striatum.

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations.

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as a major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on the pathophysiology of Parkinson's disease (PD). In line with this, alpha-syn is considered to be the guilty protein in the disease process, and it may be targeted through precision medicine to modify disease progression. Therefore, designing specific tools to block the aggregation and spreading of alpha-syn represents a major effort in the development of disease-modifying therapies in PD. The present article analyzes concrete evidence about the significance of alpha-syn within LBs. In this effort, some dogmas are challenged. This concerns the question of whether alpha-syn is more abundant compared with other proteins within LBs. Again, the occurrence of alpha-syn compared with non-protein constituents is scrutinized. Finally, the prominent role of alpha-syn in seeding LBs as the guilty structure causing PD is questioned. These revisited concepts may be helpful in the process of validating which proteins, organelles, and pathways are likely to be involved in the damage to meso-striatal dopamine neurons and other brain regions involved in PD.

Adolescents rats engage the orbitofrontal-striatal pathway differently than adults during impulsive actions.

Adolescence is characterized by increased impulsive and risk-taking behaviors. To better understand the neural networks that subserves impulsivity in adolescents, we used a reward-guided behavioral model that quantifies age differences in impulsive actions in adult and adolescent rats of both sexes. Using chemogenetics, we identified orbitofrontal cortex (OFC) projections to the dorsomedial striatum (DMS) as a critical pathway for age-related execution of impulsive actions. Simultaneous recording of single units and local field potentials in the OFC and DMS during task performance revealed an overall muted response in adolescents during impulsive actions as well as age-specific differences in theta power and OFC-DMS functional connectivity. Collectively, these data reveal that the OFC-DMS pathway is critical for age-differences in reward-guided impulsive actions and provide a network mechanism to enhance our understanding of how adolescent and adult brains coordinate behavioral inhibition.

Cortico-striatal differences in the epigenome in attention-deficit/ hyperactivity disorder.

While epigenetic modifications have been implicated in ADHD through studies of peripheral tissue, to date there has been no examination of the epigenome of the brain in the disorder. To address this gap, we mapped the methylome of the caudate nucleus and anterior cingulate cortex in post-mortem tissue from fifty-eight individuals with or without ADHD. While no single probe showed adjusted significance in differential methylation, several differentially methylated regions emerged. These regions implicated genes involved in developmental processes including neurogenesis and the differentiation of oligodendrocytes and glial cells. We demonstrate a significant association between differentially methylated genes in the caudate and genes implicated by GWAS not only in ADHD but also in autistic spectrum, obsessive compulsive and bipolar affective disorders through GWAS. Using transcriptomic data available on the same subjects, we found modest correlations between the methylation and expression of genes. In conclusion, this study of the cortico-striatal methylome points to gene and gene pathways involved in neurodevelopment, consistent with studies of common and rare genetic variation, as well as the post-mortem transcriptome in ADHD.

Volumetric analysis of age- and sex-related changes in the corpus striatum and thalamus in the 1-18 age group: a retrospective magnetic resonance imaging study.

Studies of the development and asymmetry of the corpus striatum and thalamus in early childhood are rare. Studies investigating these structures across the lifespan have not presented their changes during childhood and adolescence in detail. For these reasons, this study investigated the effect of age and sex factors on the development and asymmetry of the corpus striatum and thalamus in the 1-18 age group. In this retrospective study, we included 652 individuals [362 (56%) males] aged 1-18 years with normal brain MRI between 2012 and 2021. Absolute and relative volumes of the corpus striatum and thalamus were obtained by segmentation of three-dimensional T1-weighted MRIs with volBrain1.0. We created age-specific volume data and month-based development models with the help of SPSS (ver.28). The corpus striatum and thalamus had cubic absolute volumetric developmental models. The relative volume of the caudate and thalamus (only males) is consistent with the decreasing "growth" model, the others with the decreasing cubic model. The absolute volumes of the males' bilateral corpus striatum and thalamus and the relative volumes of the caudate and thalamus of the females were significantly larger (P < 0.05). The caudate showed right > left lateralization; putamen, globus pallidus, and thalamus showed left > right lateralization.

The following article for this Special Issue was previously published and can be found in its respective issue online: "Acetylcholine release from striatal cholinergic interneurons is controlled differently depending on the firing pattern".

Acetylcholine release from striatal cholinergic interneurons is controlled differently depending on the firing pattern (Published in JNC 167.1 issue) https://onlinelibrary.wiley.com/doi/10.1111/jnc.15950.

Parallel executive pallio-motor loops in the pigeon brain.

A core component of the avian pallial cognitive network is the multimodal nidopallium caudolaterale (NCL) that is considered to be analogous to the mammalian prefrontal cortex (PFC). The NCL plays a key role in a multitude of executive tasks such as working memory, decision-making during navigation, and extinction learning in complex learning environments. Like the PFC, the NCL is positioned at the transition from ascending sensory to descending motor systems. For the latter, it sends descending premotor projections to the intermediate arcopallium (AI) and the medial striatum (MSt). To gain detailed insight into the organization of these projections, we conducted several retrograde and anterograde tracing experiments. First, we tested whether NCL neurons projecting to AI (NCLarco neurons) and MSt (NCLMSt neurons) are constituted by a single neuronal population with bifurcating neurons, or whether they form two distinct populations. Here, we found two distinct projection patterns to both target areas that were associated with different morphologies. Second, we revealed a weak topographic projection toward the medial and lateral striatum and a strong topographic projection toward AI with clearly distinguishable sensory termination fields. Third, we investigated the relationship between the descending NCL pathways to the arcopallium with those from the hyperpallium apicale, which harbors a second major descending pathway of the avian pallium. We embed our findings within a system of parallel pallio-motor loops that carry information from separate sensory modalities to different subpallial systems. Our results also provide insights into the evolution of the avian motor system from which, possibly, the song system has emerged.

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.

Comparative Roles of the Caudate and Putamen in the Serial Order of Behavior: Effects of Striatal Glutamate Receptor Blockade on Variable versus Fixed Spatial Self-Ordered Sequencing in Marmosets.

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitoring motor feedback. Caudate infusions, however, did not affect continuous errors, but did cause an upward trend in recurrent perseveration, possibly reflecting interference with the caudate's established role in spatial working memory and goal-directed planning. In contrast to variable array performance, while both caudate and putamen infusions impaired fixed array responding, the combined effects were not additive, suggesting possible competing roles. Infusions into either region individually, but not simultaneously, led to continuous perseveration. Recurrent perseveration in fixed arrays was caused by putamen, but not caudate, infusions. These results are consistent overall with a role of caudate in planning and flexible responding and the putamen in more rigid habitual or automatic responding.

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.

Shared and Specific Changes of Cortico-Striatal Functional Connectivity in Stable Mild Cognitive Impairment and Progressive Mild Cognitive Impairment.

Background: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer's disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. Objective: We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. Methods: We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Results: Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Conclusions: Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially.

Postmortem neuropathology in early Huntington disease.

Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.

4'-fluorocannabidiol associated with capsazepine restrains L-DOPA-induced dyskinesia in hemiparkinsonian mice: Contribution of anti-inflammatory and anti-glutamatergic mechanisms.

We tested the efficacy of 4'-fluorocannabidiol (4'-F-CBD), a semisynthetic cannabidiol derivative, and HU-910, a cannabinoid receptor 2 (CB2) agonist in resolving l-DOPA-induced dyskinesia (LID). Specifically, we were interested in studying whether these compounds could restrain striatal inflammatory responses and rescue glutamatergic disturbances characteristic of the dyskinetic state. C57BL/6 mice were rendered hemiparkinsonian by unilateral striatal lesioning with 6-OHDA. Abnormal involuntary movements were then induced by repeated i.p. injections of l-DOPA + benserazide. After LID was installed, the effects of a 3-day treatment with 4'-F-CBD or HU-910 in combination or not with the TRPV1 antagonist capsazepine (CPZ) or CB2 agonists HU-308 and JWH015 were assessed. Immunostaining was conducted to investigate the impacts of 4'-F-CBD and HU-910 (with CPZ) on inflammation and glutamatergic synapses. Our results showed that the combination of 4'-F-CBD + CPZ, but not when administered alone, decreased LID. Neither HU-910 alone nor HU-910+CPZ were effective. The CB2 agonists HU-308 and JWH015 were also ineffective in decreasing LID. Both combination treatments efficiently reduced microglial and astrocyte activation in the dorsal striatum of dyskinetic mice. However, only 4'-F-CBD + CPZ normalized the density of glutamate vesicular transporter-1 (vGluT1) puncta colocalized with the postsynaptic density marker PSD95. These findings suggest that 4'-F-CBD + CPZ normalizes dysregulated cortico-striatal glutamatergic inputs, which could be involved in their anti-dyskinetic effects. Although it is not possible to rule out the involvement of anti-inflammatory mechanisms, the decrease in striatal neuroinflammation markers by 4'-F-CBD and HU-910 without an associated reduction in LID indicates that they are insufficient per se to prevent LID manifestations.

Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.

Background: Mutations in the Huntingtin (HTT) gene cause Huntington's disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood. Objective: To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations. Methods: We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic HTT knock-out human induced pluripotent stem cell (iPSC) clones. Results: We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons. Conclusions: We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons.

GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors.

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Glycine transporter-1 inhibition by NFPS promotes neuroprotection against striatal damage models.

The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage.

Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.

Transgenic tools targeting the basal ganglia reveal both evolutionary conservation and specialization of neural circuits in zebrafish.

The cortico-basal ganglia circuit mediates decision making. Here, we generated transgenic tools for adult zebrafish targeting specific subpopulations of the components of this circuit and utilized them to identify evolutionary homologs of the mammalian direct- and indirect-pathway striatal neurons, which respectively project to the homologs of the internal and external segment of the globus pallidus (dorsal entopeduncular nucleus [dEN] and lateral nucleus of the ventral telencephalic area [Vl]) as in mammals. Unlike in mammals, the Vl mainly projects to the dEN directly, not by way of the subthalamic nucleus. Further single-cell RNA sequencing analysis reveals two pallidal output pathways: a major shortcut pathway directly connecting the dEN with the pallium and the evolutionarily conserved closed loop by way of the thalamus. Our resources and circuit map provide the common basis for the functional study of the basal ganglia in a small and optically tractable zebrafish brain for the comprehensive mechanistic understanding of the cortico-basal ganglia circuit.