Corticostriatal-thalamocortical Circuits Research Articles

The neurobiology of environmentally induced stereotypic behaviours in captive animals: assessing the basal ganglia pathways and cortico-striatal-thalamo-cortical circuitry hypotheses

Abstract The neurobiology of environmentally induced stereotypic behaviours (SBs) (e.g., pacing in zoo carnivores, crib-biting in horses, tail chasing in dogs) is hypothesized to involve altered functioning within the basal ganglia (‘Basal Ganglia (BG) Pathways Hypotheses’) and/or between the basal ganglia and cortex (‘Cortico-Striatal-Thalamo-Cortical (CSTC) Circuits Hypotheses’). We review four decades of relevant studies, critically assessing support for both hypotheses. Currently no BG Pathways or CSTC Circuits hypothesis is fully supported. While some results are partially consistent with some hypotheses (decreased subthalamic nucleus activity in deer mice and C58 mice); others (nucleus accumbens activity in mink and C57 mice) seem to reflect individual differences in SB, but not environmental effects. Yet others can be tentatively rejected: neither elevated striatal dopamine nor the cortico-striatal connection of the sensorimotor circuit seem to be involved for most species studied to date. Further research is now important for understanding the impact of captivity on animals’ functioning.

Corticostriatal-limbic correlates of sub-clinical obsessive-compulsive traits

Obsessive-compulsive (OC) traits such as intrusive worrisome ideas or excessive concerns for threats are frequent in general population (5%–13%). However, the structural neural correlates of the sub-clinical OC traits remain largely unknown. Based on the data of obsessive-compulsive disorder (OCD), we hypothesized that the subcortical and cortical structures, constituting the cortico-striatal-thalamo-cortical circuit (CSTC) and the limbic system, could be associated with OC traits. Here we conducted voxel-based morphometry (VBM) in order to investigate fine grained volume changes of these structures in 49 non-clinical subjects. Analysis of structural covariances of these structures was also conducted. We identified volume changes associated with OC traits in the left putamen and the left amygdala. The results of structural covariance analysis revealed increased covariances in relation to the heightened OC traits between the left putamen to bilateral medial prefrontal cortex and to the left cerebellum, and between the left globus pallidus to the bilateral anterior cingulate cortices. The present finding of volume changes of the corticostriatal-limbic structures may reflect neuroplasticity associated with OC traits. Since the abnormality of these structures were also observed in the clinical OCD, the subclinical subjects with OC traits shared “neuronal obsessive traits” that might precondition OCD at the network level.

Soluble interleukin-6 receptor induces motor stereotypies and co-localizes with gp130 in regions linked to cortico-striato-thalamo-cortical circuits.

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity and whose levels are increased in states of immune activation. Soluble interleukin-6 receptor (sIL-6R) levels positively correlate with disease progression in some autoimmune conditions and psychiatric disorders. Particularly strong links between levels of sIL-6R and the severity of psychotic symptoms occur in schizophrenia, raising the possibility that sIL-6R is involved in this disease. However, there is no evidence that peripheral sIL-6R induces relevant behavioral disturbances. We showed that single subcutaneous injections of sIL-6R (0–1 µg), stimulated novelty stress-induced exploratory motor behaviors in male Balb/c mice within 20–40-min of injection. A progressive increase in vertical stereotypies was observed 40–80 min post injection, persisting for the remainder of the test session. Paralleling these stimulant-like effects, sIL-6R pre-treatment significantly enhanced stereotypy scores following challenge with GBR 12909. We found that peripherally administered sIL-6R crossed the blood-brain barrier, localizing in brain regions associated with cortico-striatal-thalamo-cortical (CSTC) circuits, which are putative neuroanatomical substrates of disorders associated with repetitive stereotypies. Peripherally administered sIL-6R co-localized with gp130, a transmembrane protein involved in IL-6 trans-signaling, in the nucleus accumbens, caudate-putamen, motor and infralimbic cortices, and thalamic nuclei, but not with gp130 in the ventral tegmental area, substantia nigra, or sensorimotor cortex,. The results suggest that peripheral sIL-6R can act as a neuroimmune messenger, crossing the blood brain barrier (BBB) to selectively target CSTC circuits rich in IL-6 trans-signaling protein, and inducing repetitive stereotypies. As such sIL-6R may represent a novel therapeutic agent for relevant psychiatric disorders.

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ∼5-7 years, and the majority of children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioral and pharmacological approaches. Evidence supports TS being an inherited disorder; however, the precise genetic abnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.

Estimulación cerebral profunda talámica para la epilepsia resistente

Epilepsy is a neurological disorder that affects 1-2% of the population. Despite the available treatments (drug therapy, resective surgery, vagus nerve stimulation), there is a significant subgroup of patients that continues to have disabling seizures. The indications of deep brain stimulation are exponentially growing, and there is a wide experience with deep brain stimulation (DBS) for the treatment of abnormal movements. DBS for epilepsy may be a new therapy for the subgroup of patients that remain disabled despite other treatments. Experiments with animal models, and the new advances in our knowledge about the neurophysiological processes that govern the genesis of epilepsy, have led to the selection of various brain targets for stimulation. The thalamus is a fundamental relay centre in the corticothalamic and corticostriatal thalamocortical circuits, and it has been studied with this purpose. Studies on epileptic patients have shown various degrees of effectiveness; however, controlled studies do not permit definitive conclusions about the role of DBS in the treatment of epilepsy. Probably a better patient selection would lead to more decisive conclusions. Further randomised studies are needed to draw reliable conclusions and scientific evidence on the effectiveness of DBS for refractory epilepsy.

An Update on Tourette Syndrome

Recent advances in our understanding of the phenomenology, etiology, pathophysiology, and treatment of Tourette syndrome are discussed. Tourette syndrome appears to involve dysfunction of limbic and somatosensory "traffic" through the basal ganglia, within corticostriatal-thalamocortical circuits. Dynamic alterations in the balance of these inputs may dictate the manifestations (sensory, motor, affective, and behavioral) of the disorder at any given time. Individualized assessment and treatment are the keys to optimal treatment of this condition.

Glutamatergic modulatory therapy for Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the presence of chronic, fluctuating motor and vocal (phonic) tics. The disorder is commonly associated with a variety of comorbidities including obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), school problems, anxiety, and depression. Therapeutically, if tics are causing psychosocial or physical problems, symptomatic medications are often prescribed, typically alpha-adrenergic agonists or dopamine antagonists. Recognizing that therapy is often ineffective and frequently associated with unacceptable side-effects, there is an ongoing effort to identify new tic-suppressing therapies. Several lines of evidence are presented that support the use of glutamate modulators in TS including glutamate’s major role in cortico-striatal-thalamo-cortical circuits (CSTC), the recognized extensive interaction between glutamate and dopamine systems, results of familial genetic studies, and data from neurochemical analyses of postmortem brain samples. Since insufficient data is available to determine whether TS is definitively associated with a hyper- or hypo-glutamatergic state, potential treatment options using either glutamate antagonists or agonists are reviewed. Data from studies using these agents in the treatment of OCD are presented. If validated, modulation of the glutamate system could provide a valuable new pharmacological approach in the treatment of tics associated with Tourette syndrome.

Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome

Tourette syndrome (TS) is an inherited developmental neuropsychiatric disorder characterized by vocal and motor tics. Multiple lines of neurophysiological evidence implicate dysfunction in the corticostriatal-thalamocortical circuits in the etiology of TS. We recently identified rare sequence variants in the Slit and Trk-like family member 1 (SLITRK1) gene associated with TS. SLITRK1, a single-pass transmembrane protein, displays similarities to the SLIT family of secreted ligands, which have roles in axonal repulsion and dendritic patterning, but its function and developmental expression remain largely unknown. Here we provide evidence that SLITRK1 has a developmentally regulated expression pattern in projection neurons of the corticostriatal-thalamocortical circuits. SLITRK1 is further enriched in the somatodendritic compartment and cytoplasmic vesicles of cortical pyramidal neurons in mouse, monkey, and human brain, observations suggestive of an evolutionarily conserved function in mammals. SLITRK1 is transiently expressed in the striosomal/patch compartment of the mammalian striatum and moreover is associated with the direct output pathway; adult striatal expression is confined to cholinergic interneurons. These analyses demonstrate that the expression of SLITRK1 is dynamic and specifically associated with the circuits most commonly implicated in TS and related disorders, suggesting that SLITRK1 contributes to the development of corticostriatal-thalamocortical circuits.

Glutamatergic Synaptic Dysfunction and Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition estimated to afflict 1-3% of the world population. The estimated financial impact in the treatment and management of OCD is in the billions of dollars annually in the US alone. At present there is a marked lack of evidence on the specific causes of OCD. Current hypotheses largely focus on the serotonin (5-HT) system on the basis of the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in alleviating symptoms of patients with OCD, yet a considerable fraction of patients are non-responsive or minimally responsive to these agents. Despite this fact, SSRIs have remained the primary pharmacological treatment avenue for OCD. In recent years, multiple lines of evidence have implicated glutamatergic synaptic dysfunction within the cortico-striatal-thalamo-cortical (CSTC) brain circuit in the etiology of OCD and related disorders, thereby prompting intensified effort in the development and evaluation of agents that modulate glutamatergic neurotransmission for the treatment of OCD. With this in mind, here we review the following topics with respect to synaptic dysfunction and the neural circuitry underlying OCD: (1) evidence supporting the critical involvement of the CSTC circuit, (2) genetic studies supporting the involvement of glutamatergic dysfunction, (3) insights from genetic animal models of OCD, and (4) preliminary findings with glutamatergic neurotransmission-modulating agents in the treatment of OCD. Given the putative mechanistic overlap between OCD and the broader OC-spectrum of disorders, unraveling the synaptic basis of OCD has potential to translate into more effective treatments for an array of poorly understood human disorders.

Temporal Dynamics of Cortical and Subcortical Responses to Apomorphine in Parkinson Disease

H2(15)O positron emission tomography (PET) was used to study the temporal course of central nervous system (CNS) responses to apomorphine in patients with idiopathic Parkinson disease (PD). Agonist-induced changes in regional cerebral blood flow (rCBF) were evaluated within corticostriatal-thalamocortical circuits as well as in regions that extend beyond the standard pathophysiological model for PD. Compared with controls, rCBF was increased in PD patients in subcortical regions including the basal ganglia and cerebellum and both increased and decreased in prefrontal, parietal, sensorimotor, and paralimbic cortical areas. Apomorphine reversed many of these effects and had widespread effects throughout the brain. We evaluated the effects of apomorphine as they changed over time, comparing rCBF before the motor response and at later times when the motor response was maximal. Apomorphine's effects on functional connectivity also changed over time; activity in the ventrolateral thalamus was coupled with that in the SMA and cerebellum at the time of maximum motor response, but not at 45 seconds. Apomorphine affected rCBF in regions commonly considered part of the pathophysiological model of PD (eg, basal ganglia, thalamus, SMA), and other effects were seen in regions outside of the model (eg, cerebellum and superior parietal lobule). Results are discussed in light of this model.

Neural systems for sign language production: Mechanisms supporting lexical selection, phonological encoding, and articulation

Overt production of ASL signs was evaluated using H(2)(15)O PET to differentiate brain systems that support sign language production at the lexical-selection and phonological-articulatory levels. Subjects were 16 right-handed, congenitally deaf native ASL signers (10 women, six men; age 20 to 29 years). Scans were performed while subjects (1) passively viewed ASL nouns, (2) repeated nouns, (3) generated verbs in response to these nouns, (4) passively viewed videotaped segments depicting transitive actions, and (5) generated a verb to describe these actions. Conjunctions between the two verb-generation tasks revealed left-lateralized activation of perisylvian, frontal, and subcortical regions commonly observed in spoken language generation tasks and implicated in processes of semantic feature binding and lexical selection. Analysis of noun repetition minus viewing condition revealed activation of distinct systems supporting phonological encoding and articulation, including bilateral activation of sensorimotor areas and association cortices in the temporal, parietal, and occipital lobes. In addition, lexical-selection and articulatory processes were associated with activation of different corticostriatal-thalamocortical circuits: articulation with activation of the motor, and lexical-selection with activation of the prefrontal circuits, respectively. The results collectively provide insight into dissociable neural systems underlying these psycholinguistic functions. In addition, activation of regions that are typically associated with the auditory system during sign production suggests that these regions may support modality-independent linguistic processes, or may indicate cross-modal plasticity within the deaf brain.