Fetuin, a fetal plasma glycoprotein, has been shown previously to be present in sub-populations of neurons in the developing central and peripheral nervous system. To gain a more complete description of the time course of the appearance of fetuin during neurogenesis we have examined fetuin immunoreactivity, and the presence of fetuin mRNA, in the developing rat trigeminal and dorsal root ganglia. Fetuin immunoreactivity and its mRNA were first seen at embryonic day 15 in the trigeminal ganglia, and at embryonic day 16 in dorsal root ganglia. In both trigeminal and dorsal root ganglion, fetuin appeared to be present up until around the time of birth, and then again between postnatal days 3 and 16. The results suggest that fetuin first appears at around the time that ganglion cell axons reach their central targets, which is also approximately when the cell-death period begins. The proportion of ganglion neurons that were fetuin immunoreactive at different ages was inversely related to the amount of cell death that is known to occur in these populations, thus it seems that fetuin is more likely to be associated not with dying cells, but with those that survive the cell-death period.

With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF).

Recent studies have shown that temporal stability of the neuronal activity over time can be estimated by the structure of the spike-count autocorrelation of neuronal populations. This estimation, called the intrinsic timescale, has been computed for several cortical areas and can be used to propose a cortical hierarchy reflecting a scale of temporal receptive windows between areas. In this study, we performed an autocorrelation analysis on neuronal populations of three basal ganglia (BG) nuclei, including the striatum and the subthalamic nucleus (STN), the input structures of the BG, and the external globus pallidus (GPe). The analysis was performed during the baseline period of a motivational visuomotor task in which monkeys had to apply different amounts of force to receive different amounts of reward. We found that the striatum and the STN have longer intrinsic timescales than the GPe. Moreover, our results allow for the placement of these subcortical structures within the already-defined scale of cortical temporal receptive windows. Estimates of intrinsic timescales are important in adding further constraints in the development of computational models of the complex dynamics among these nuclei and throughout cortico-BG-thalamo-cortical loops.

Recent studies have shown that the cerebellum and the basal ganglia are interconnected at subcortical levels. However, a subcortical basal ganglia connection to the inferior olive (IO), being the source of the olivocerebellar climbing fiber system, is not known. We have used classical tracing with CTb, retrograde transneuronal infection with wildtype rabies virus, conditional tracing with genetically modified rabies virus, and examination of material made available by the Allen Brain Institute, to study potential basal ganglia connections to the inferior olive in rats and mice. We show in both species that parvalbumin-positive, and therefore GABAergic, neurons in the entopeduncular nucleus, representing the rodent equivalent of the internal part of the globus pallidus, innervate a group of cells that surrounds the fasciculus retroflexus and that are collectively known as the area parafascicularis prerubralis. As these neurons supply a direct excitatory input to large parts of the inferior olivary complex, we propose that the entopeduncular nucleus, as a main output station of the basal ganglia, provides an inhibitory influence on olivary excitability. As such, this connection may influence olivary involvement in cerebellar learning and/or could be involved in transmission of reward properties that have recently been established for olivocerebellar signaling.

We report the case of a patient with idiopathic hypoparathyroidism and unusually large symmetrical calcifications in the basal ganglia, thalami, cerebellar hemispheres and brainstem, who clinically presented an ALS-like syndrome. We discuss the possible role of abnormal calcium metabolism in the pathogenesis of motoneuron disease.

This study aimed to provide a first detailed description of the serotonin (5-hydroxytryptamine, 5-HT) innervation of the human basal ganglia under nonpathological conditions. We applied an immunohistochemical approach to postmortem human brain material with antibodies directed against the 5-HT transporter and the 5-HT-synthesizing enzyme (tryptophane hydroxylase) to visualize 5-HT axons and cell bodies, respectively. Adjacent sections were immunostained for tyrosine hydroxylase to compare the distribution of 5-HT axons with that of dopamine axons. Human basal ganglia are innervated by 5-HT axons that emerge chiefly from the dorsal and, less abundantly, from the median raphe nuclei. These axons form thick ascending fascicles that fragment themselves as they penetrate the decussation of the superior cerebellar peduncle. They regroup within the ventral tegmental area and ascend along the medial forebrain bundle, immediately beneath the dopamine ascending fibers. At regular intervals along their course, 5-HT axons detach themselves from the medial forebrain bundle and sweep laterally to arborize within all basal ganglia components, where they display highly variable densities and patterns of innervation. The substantia nigra is the most densely innervated component of the basal ganglia, whereas the caudate nucleus is more heterogeneously innervated than the putamen and pallidum. The subthalamic nucleus harbors 5-HT-immunoreactive fibers that display a mediolateral-decreasing gradient. The fact that all components of human basal ganglia receive a dense 5-HT input indicates that, in concert with dopamine, 5-HT plays a crucial role in the functional organization of these motor-related structures, which are often targeted in neurodegenerative diseases.

The specific functions of sensory systems depend on the tissue-specific expression of genes that code for molecular sensor proteins that are necessary for stimulus detection and membrane signaling. Using the Next Generation Sequencing technique (RNA-Seq), we analyzed the complete transcriptome of the trigeminal ganglia (TG) and dorsal root ganglia (DRG) of adult mice. Focusing on genes with an expression level higher than 1 FPKM (fragments per kilobase of transcript per million mapped reads), we detected the expression of 12984 genes in the TG and 13195 in the DRG. To analyze the specific gene expression patterns of the peripheral neuronal tissues, we compared their gene expression profiles with that of the liver, brain, olfactory epithelium, and skeletal muscle. The transcriptome data of the TG and DRG were scanned for virtually all known G-protein-coupled receptors (GPCRs) as well as for ion channels. The expression profile was ranked with regard to the level and specificity for the TG. In total, we detected 106 non-olfactory GPCRs and 33 ion channels that had not been previously described as expressed in the TG. To validate the RNA-Seq data, in situ hybridization experiments were performed for several of the newly detected transcripts. To identify differences in expression profiles between the sensory ganglia, the RNA-Seq data of the TG and DRG were compared. Among the differentially expressed genes (> 1 FPKM), 65 and 117 were expressed at least 10-fold higher in the TG and DRG, respectively. Our transcriptome analysis allows a comprehensive overview of all ion channels and G protein-coupled receptors that are expressed in trigeminal ganglia and provides additional approaches for the investigation of trigeminal sensing as well as for the physiological and pathophysiological mechanisms of pain.

How movements are selected is a fundamental question in systems neuroscience. While many studies have elucidated the sensorimotor transformations underlying stimulus-guided movements, less is known about how internal goals - critical drivers of goal-directed behavior - guide movements. The basal ganglia are known to bias movement selection according to value, one form of internal goal. Here, we examine whether other internal goals, in addition to value, also influence movements via the basal ganglia. We designed a novel task for mice that dissociated equally rewarded internally-specified and stimulus-guided movements, allowing us to test how each engaged the basal ganglia. We found that activity in the substantia nigra pars reticulata, a basal ganglia output, predictably differed preceding internally-specified and stimulus-guided movements. Incorporating these results into a simple model suggests that internally-specified movements may be facilitated relative to stimulus-guided movements by basal ganglia processing.

The cerebellum and the basal ganglia are major subcortical nuclei that control multiple aspects of behavior largely through their interactions with the cerebral cortex. Discrete multisynaptic loops connect both the cerebellum and the basal ganglia with multiple areas of the cerebral cortex. Interactions between these loops have traditionally been thought to occur mainly at the level of the cerebral cortex. Here, we review a series of recent anatomical studies in nonhuman primates that challenge this perspective. We show that the anatomical substrate exists for substantial interactions between the cerebellum and the basal ganglia. Furthermore, we discuss how these pathways may provide a useful framework for understanding cerebellar contributions to the manifestation of two prototypical basal ganglia disorders, Parkinson's disease and dystonia.

The basal ganglia are important for action selection. They are also implicated in perceptual and cognitive functions that seem far removed from motor control. Here, we tested whether the role of the basal ganglia in selection extends to nonmotor aspects of behavior by recording neuronal activity in the caudate nucleus while animals performed a covert spatial attention task. We found that caudate neurons strongly select the spatial location of the relevant stimulus throughout the task even in the absence of any overt action. This spatially selective activity was dependent on task and visual conditions and could be dissociated from goal-directed actions. Caudate activity was also sufficient to correctly identify every epoch in the covert attention task. These results provide a novel perspective on mechanisms of attention by demonstrating that the basal ganglia are involved in spatial selection and tracking of behavioral states even in the absence of overt orienting movements.

Suppressing actions is essential for flexible behavior. Multiple neural circuits involved in behavioral inhibition converge upon a key basal ganglia output nucleus, the substantia nigra pars reticulata (SNr). To examine how changes in basal ganglia output contribute to self-restraint, we recorded SNr neurons during a proactive behavioral inhibition task. Rats responded to Go! cues with rapid leftward or rightward movements, but also prepared to cancel one of these movement directions on trials when a Stop! cue might occur. This action restraint - visible as direction-selective slowing of reaction times - altered both rates and patterns of SNr spiking. Overall firing rate was elevated before the Go! cue, and this effect was driven by a subpopulation of direction-selective SNr neurons. In neural state space, this corresponded to a shift away from the restrained movement. SNr neurons also showed more variable inter-spike intervals during proactive inhibition. This corresponded to more variable state-space trajectories, which may slow reaction times via reduced preparation to move. These findings open new perspectives on how basal ganglia dynamics contribute to movement preparation and cognitive control.

The basal ganglia and cerebellum are major subcortical structures that influence not only movement, but putatively also cognition and affect. Both structures receive input from and send output to the cerebral cortex. Thus, the basal ganglia and cerebellum form multisynaptic loops with the cerebral cortex. Basal ganglia and cerebellar loops have been assumed to be anatomically separate and to perform distinct functional operations. We investigated whether there is any direct route for basal ganglia output to influence cerebellar function that is independent of the cerebral cortex. We injected rabies virus (RV) into selected regions of the cerebellar cortex in cebus monkeys and used retrograde transneuronal transport of the virus to determine the origin of multisynaptic inputs to the injection sites. We found that the subthalamic nucleus of the basal ganglia has a substantial disynaptic projection to the cerebellar cortex. This pathway provides a means for both normal and abnormal signals from the basal ganglia to influence cerebellar function. We previously showed that the dentate nucleus of the cerebellum has a disynaptic projection to an input stage of basal ganglia processing, the striatum. Taken together these results provide the anatomical substrate for substantial two-way communication between the basal ganglia and cerebellum. Thus, the two subcortical structures may be linked together to form an integrated functional network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

The basal ganglia involve in a range of functions that are disturbed in schizophrenia patients. This study decomposed the resting-state data of 28 schizophrenia patients and 31 healthy controls with spatial independent component analysis and identified increased functional integration in the bilateral caudate nucleus in schizophrenia patients. Further, the caudate nucleus in patients showed altered functional connection with the prefrontal area and cerebellum. These results identified the importance of basal ganglia in schizophrenia patients.

The entopeduncular nucleus is one of the basal ganglia's output nuclei, thereby controlling basal ganglia information processing. Entopeduncular nucleus neurons integrate GABAergic inputs from the Striatum and the globus pallidus, together with glutamatergic inputs from the subthalamic nucleus. We show that endocannabinoids and dopamine interact to modulate the long-term plasticity of all these primary afferents to the entopeduncular nucleus. Our results suggest that the interplay between dopamine and endocannabinoids determines the balance between direct pathway (striatum) and indirect pathway (globus pallidus) in entopeduncular nucleus output. Furthermore, we demonstrate that, despite the lack of axon collaterals, information is transferred between neighboring neurons in the entopeduncular nucleus via endocannabinoid diffusion. These results transform the prevailing view of the entopeduncular nucleus as a feedforward "relay" nucleus to an intricate control unit, which may play a vital role in the process of action selection.

The mammalian subthalamic nucleus (STN) is a glutamatergic cell group within the indirect pathway of the basal ganglia. It receives input from the external globus pallidus (GP) and in turn projects to the internal GP and the substantia nigra pars reticulata (SNr). While the direct pathway from striatum to SNr is well established in anurans, it is unknown whether they possess an indirect pathway including a STN homologue. The subthalamic region comprises the dorsocaudal suprachiasmatic nucleus (dcSC), the posterior entopeduncular nucleus (EP), and the ventral part of the ventral thalamus (vVM/VL). In the fire-bellied toad Bombina orientalis we investigated whether one of these areas match the criteria established for the mammalian STN. We delineated the SNr in the midbrain tegmentum by labeling the striatonigral terminal field by means of GABA-, substance P-, and enkephalin immunohistochemistry and striatal tracer injections. Subsequently, we used double fluorescence tracing with injections into the SNr and GP to stain different parts of the indirect pathway. Confocal laser scan analysis revealed that dcSC, EP, and vVM/VL contain retrogradely labeled neurons projecting to the SNr, contacted by anterogradely labeled terminals arising in the GP. Immunohistochemical stainings with antibodies against glutamate and the glutamate transporters EAAC1 and vGluT2 demonstrated that the investigated nuclei contain glutamatergic neurons. Our results suggest that all regions in the subthalamic region fulfill our morphological criteria, except the connection back to the GP. An indirect basal ganglia pathway seems to be present in anuran amphibians, although we cannot exclusively delineate an STN homologue.

Although the cortical substrates of verbal working memory are reasonably well understood, less is known about the relative contribution of subcortical structures to verbal working memory. Therefore, in addition to elaboration of a model of verbal working memory by including a specific focus on basal ganglia, the purpose of this study also was to examine potential differences in neural function across the complete process of verbal working memory, from encoding through retrieval. Functional magnetic resonance imaging was used to observe regions of brain activation in neurologically normal participants during a task of verbal working memory. The expected frontal-parietal network was found to be active over the course of the verbal working memory task. The encoding portion of the task engaged left inferior frontal regions and bilateral caudate and thalamus. Bilateral medial thalamus and posterior cingulate regions were engaged during the maintenance phase of the task. Retrieval activated the left inferior frontal sulcus and posterior parietal/occipital regions. Findings are considered in light of current models of verbal working memory and subcortical structures.

Friedreich ataxia (FA) causes distinctive lesions of dorsal root ganglia (DRG), including neuronal atrophy, satellite cell hyperplasia, and absorption of dying nerve cells into residual nodules. Two mechanisms may be involved: hypoplasia of DRG neurons from birth and superimposed iron (Fe)- and zinc (Zn)-mediated oxidative injury. This report presents a systematic analysis of DRG in 7 FA patients and 13 normal controls by X-ray fluorescence (XRF) of polyethylene glycol-embedded DRG; double-label confocal immunofluorescence microscopy of Zn- and Fe-related proteins; and immunohistochemistry of frataxin and the mitochondrial marker, ATP synthase F1 complex V β-polypeptide (ATP5B).

Primary dorsal root ganglia (DRG) neurons are often used to investigate the relative strength of various guidance cues to promote re-growth in vitro. Current methods of neuron isolation are laborious and disposal of excess dissected cells is inefficient. Traditional immunostaining techniques are inadequate to visualize real-time neurite outgrowth in co-culture. Cryopreservation, in combination with transfection techniques, may provide a viable solution to both under-utilized tissue and insufficient methods of visualization. This study aims to qualitatively and quantitatively demonstrate successful cryopreservation of primary transfected and non-transfected DRG neurons. Fluorescent micrographs were used to assess morphology after 24h in culture and suggest similarities between freshly isolated neurons and neurons which have been transfected and/or cryopreserved. Quantitative measurements of neuron outgrowth (specifically, primary neurites, branch points and total neurite length) indicate that neuron outgrowth is not altered by cryopreservation. Transfected neurons have stunted outgrowth at 24h.

Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson's disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects.