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Network-level neuroplasticity in cortico-basal ganglia pathways
Abstract
The striatum, the largest input nucleus of the basal ganglia, receives massive inputs from the neocortex and thalamus, and gives rise to the direct, indirect and striosomal pathways of the basal ganglia. Here, the view is developed that the striatum is a major site for adaptive plasticity in cortico-basal ganglia circuits, affecting in the normal state a broad range of behaviours. This plasticity can become a major source of maladaptive responses in disease states affecting the basal ganglia. (C) 2004 Published by Elsevier Ltd.
... Although the cortical control of movement is well documented (Kalaska et al., 1997;Taylor et al., 2002;Carmena et al., 2003;Andersen et al., 2004;Donoghue et al., 2005;Lebedev et al., 2008;Nicolelis and Lebedev, 2009), the interaction between cortex and striatum is also relevant. This is mainly because the striatum receives input from topographic projections (that are responsible for turning relevant behaviors on and off, depending on the behavioral context), from roughly 90% of the cortex (Bolam et al., 2000;Graybiel, 2004;DeLong and Wichmann, 2007). While dorsal striatum integrates information from multiple brain regions (Wall et al., 2013) to shape motor learning and habit formation, the interface between cortex and striatum is not well understood. ...
... An important reason we looked into this aspect stems from the fact that disruption of cortico-striatal circuits compromises the functionality of these circuits, resulting in a multitude of neurologic disorders, including Parkinson's disease (PD). PD is one of the most devastating neurodegenerative disorders, with no cure and limited treatment (Camicioli, 1993;Graybiel, 2004). PD is characterized by symptoms that include tremors and muscle stiffness with strong cortical-basal beta (15-30 Hz) oscillation in human and animal models (Leventhal et al., 2012). ...
... The same method of analysis (Vaadia et al., 1995) was used to test a similar hypothesis after cocaine administration, with respect to the functional connection between motor cortex and striatum during the DMS task. Indeed, this question has been addressed previously (Albin et al., 1989;Camicioli, 1993;Graybiel, 2004), but has not been examined in behaving animals where those regions were recorded simultaneously. Furthermore, in the motor-striatal neuron pairs, opposite effects were observed in the cross-correlations under baclofen vs. cocaine Neurons in both cortical areas (S1, M1) and the medial striatum (CPu.b) ...
The motor cortex and dorsal striatum (caudate nucleus and putamen) are key regions in motor processing but the interface between the cortex and striatum is not well understood. While dorsal striatum integrates information from multiple brain regions to shape motor learning and habit formation, the disruption of cortico-striatal circuits compromises the functionality of these circuits resulting in a multitude of neurologic disorders, including Parkinson's disease. To better understand the modulation of the cortico-striatal circuits we recorded simultaneously single neuron activity from four brain regions, primary motor, and sensory cortices, together with the rostral and caudal segments of the putamen in rhesus monkeys performing a visual motor task. Results show that spatial and temporal-task related firing relationships between these cortico-striatal circuit regions were modified by the independent administration of the two drugs (cocaine and baclofen). Spatial tuning and correlated firing of neurons from motor cortex and putamen were severely disrupted by cocaine and baclofen on correct trials, while the two drugs have dramatically decreased the functional connectivity of the motor cortical-striatal network. These findings provide insight into the modulation of cortical-striatal firing related to movement with implications for therapeutic approaches to Parkinson's disease and related disorders.
... Over the past decades, it became clear that striatal projection neurons, the so-called medium spiny neurons (MSNs), undergo complex structural changes in the density, morphology and ultrastructural features of their dendritic spines in animal models of Parkinson's disease (PD) or after chronic exposure to cocaine or other psychostimulants (Table 1). In PD, nigrostriatal dopamine degeneration results in a significant loss of dendritic spines on MSNs of the dorsal striatum Ingham et al, 1989Ingham et al, , 1998Anglade et al., 1996;Stephens et al., 2005;Zaja-Milatovic et al., 2005;Day et al., 2006;Deutch et al., 2007;Villalba et al., 2009;Villalba and Smith, 2010), while rodents chronically treated with dopamine-enhancing drugs such as cocaine and other psychostimulants, display significant increases in spine density on MSNs in the nucleus accumbens (Robinson and Kolb, 1997, 2001, 2004Norrholm et al. 2003;Lee et al. 2006;Kalivas 2007a,b;Russo et al., 2009;Shen et al., 2009). Together, these data strongly suggest that the opposite changes in striatal dopamine (DA) release in these disorders may play a major role in mediating differential effects towards spine development, pruning and morphogenesis in striatal projection neurons in PD and addiction to psychostimulants (Arbuthnot et al., 1998;Robinson and Kolb, 1999a;Day et al., 2006;Deutch et al., 2007;Surmeier et al., 2007;Villalba et al., 2009;Garcia et al., 2010;Fasano et al., 2013) (Fig. 1). ...
... The striatum is the main entry of extrinsic information to the basal ganglia circuitry being the target of massive glutamatergic inputs from the cerebral cortex and thalamus, as well as robust dopaminergic afferents from the ventral midbrain (Kemp and Powell, 1971a,b,c;Smith and Bolam, 1990;Parent and Hazrati, 1995;Smith et al. 1998Smith et al. , 2004Bolam et al., 2000;Nicola et al., 2000;Graybiel, 2004;Surmeier et al., 2010;Gerfen and Surmeier, 2011). Based on its sources of cortical information, the striatum is generally divided into a dorsal and ventral component characterized by segregated information processing. ...
In the striatum, the dendritic tree of the two main populations of projection neurons, called "Medium Spiny Neurons (MSNs)", are covered with spines that receive glutamatergic inputs from the cerebral cortex and thalamus. In Parkinson's disease (PD), striatal MSNs undergo an important loss of dendritic spines, whereas aberrant overgrowth of striatal spines occurs following chronic cocaine exposure. This review examines the possibility that opposite dopamine dysregulation is one of the key factors that underlies these structural changes. In PD, nigrostriatal dopamine degeneration results in a significant loss of dendritic spines in the dorsal striatum, while rodents chronically exposed to cocaine and other psychostimulants, display an increase in the density of "thin and immature" spines in the nucleus accumbens (NAc). In rodent models of PD, there is evidence that D2 dopamine receptor-containing MSNs are preferentially affected, while D1-positive cells are the main targets of increased spine density in models of addiction. However, such specificity remains to be established in primates. Although the link between the extent of striatal spine changes and the behavioral deficits associated with these disorders remains controversial, there is unequivocal evidence that glutamatergic synaptic transmission is significantly altered in both diseased conditions. Recent studies have suggested that opposite calcium-mediated regulation of the transcription factor myocyte enhancer factor 2 (MEF2) function induces these structural defects. In conclusion, there is strong evidence that dopamine is a major, but not the sole, regulator of striatal spine pathology in PD and addiction to psychostimulants. Further studies of the role of glutamate and other genes associated with spine plasticity in mediating these effects are warranted.
... The substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi) are the output nuclei of the BG receiving converging entries from both direct and indirect BG pathways (Alexander et al. 1986;Alexander and Crutcher 1990;Radnikow and Misgeld 1998;Smith et al. 1998;Ibañez-Sandoval et al. 2006;Deniau et al. 2007). Probably a choice of whether an action is executed or not occurs in these nuclei (Sarvestani et al. 2011), since according to the "two pathways model" (Albin et al. 1989), direct pathway activation facilitates, whereas indirect pathway activation represses movements (Wichmann and DeLong 2003;Graybiel 2004;Grillner et al. 2005;DeLong and Wichmann 2007;Ibañez-Sandoval et al. 2007;Bateup et al. 2010;Kravitz et al. 2010). As in other systems, synaptic plasticity is a good candidate to comprise the mechanism that makes the selection Malenka 2007, 2008;Shen et al. 2008;Di Filippo et al. 2009). ...
... This latter action may become LTD. NMDA receptors may be activated by other afferents to SNr. and tasks (Takakusaki et al. 2003(Takakusaki et al. , 2004Graybiel 2004Graybiel , 2008Yin and Knowlton 2006;Wickens 2009;Surmeier et al. 2011); they may be the port that allows one or the other to pass (Sarvestani et al. 2011), thus making action selection. Therefore, in agreement with the present experimental data, we would like to propose, as a first approximation, that each SNr neuron may act as a logical binary gate with two main inputs (see Table 1): direct and indirect BG pathways. ...
... There is evidence that the therapeutic use of an mGluR5 antagonist led to normalization of glutamate neurotransmission in the PD brain and prevented the occurrence of LID (Morin et al., 2013c). Previous studies showed that LID can be viewed as a result of aberrant dopamine-related neural plasticity at glutamate corticostriatal synapses in the striatum (Graybiel, 2004). Consistent with the notion, our results showed that motor complications induced by administration of L-DOPA are accompanied by the enrichment of the corticostriatal synaptic ultrastructures and signaling proteins in 6-OHDA-lesioned hemiparkinsonian rats, while coadministration of L-DOPA and MPEP ameliorated motor complications with a reduction in the enrichment of ultrastructures and the expression of postsynaptic proteins (PSD-95 and SAP102). ...
... Previous studies showed that LID may be due to aberrant brain plasticity (Graybiel, 2004). By using electron microscopy techniques, we examined the morphologic changes in corticostriatal synaptic ultrastructures and signaling proteins in the striatum of PD or LID rats. ...
Levodopa (L-DOPA) is still the most effective drug for the treatment of Parkinson's disease (PD). However, the long-term therapy often triggers L-DOPA-induced dyskinesia (LID). Metabotropic glutamate receptor type 5 (mGluR5) is abundant in the basal ganglia, and its inhibition is thought to modulate postsynaptic excitatory synaptic transmission and glutamate hyperactivity in PD and LID. In this report, we examined the effects of mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on LID and synaptic components in the PD model rat. We found the selective mGluR5 antagonist MPEP attenuated abnormal involuntary movements, prolonged the duration of rotational response, reversed the decrease of left forepaw adjusting steps, and reduced overexpression of striatal mGluR5 in the LID rats. Moreover, our results showed much thicker postsynaptic densities, narrower synapse cleft, as well as the increased ratio of perforated synapses induced by L-DOPA treatment, while coadministration of L-DOPA and MPEP reversed these postsynaptic effects. Finally, MPEP reduced overexpression of the two postsynaptic proteins (PSD-95 and SAP102) induced by L-DOPA treatment. Hence, these results provide evidence that aberrant neural plasticity at corticostriatal synapses in the striatum is closely correlated with the occurrence of LID, and targeted inhibition of mGluR5 by MPEP alleviates LID in the PD rat model.
... These findings are consistent with the results of studies suggesting increased cerebral hyperexcitability as a trigger for a migraine attack [8,9]. Several groups could demonstrate that the basal ganglia are responsible for adaptive plasticity in the brain, affecting behavioral [24], neurological, and psychiatric conditions [25], including pain [26]. Furthermore, the basal ganglia seem to be involved in the integration of information between the cortical and thalamic regions and the three main domains of pain processing-sensory, emotional/cognitive, and endogenous/modulatory [27]. ...
Recent neuroimaging studies have revealed important aspects of the underlying pathophysiological mechanisms of migraine suggesting abnormal brain energy metabolism and altered functional connectivity. Proton magnetic resonance spectroscopy (1H-MRS) studies investigated migraine patients in the interictal or ictal state. This first-of-its-kind study aimed to investigate the whole migraine cycle using 1H-MRS and resting-state functional magnetic resonance imaging (fMRI). A migraine patient underwent 1H-MRS and resting-state fMRI for 21 consecutive days, regardless of whether he was in an interictal or ictal state. Metabolite ratios were assessed and compared to the intrinsic connectivity of subcortical brain areas. Probable migraine phase-dependent changes in N-acetyl aspartate (NAA)/total creatine (tCr) and choline (Cho)/tCr levels are found in the left occipital lobe and left basal ganglia. NAA reflects neuronal integrity and Cho cellular membrane turnover. Such abnormalities may increase the susceptibility to excitatory migraine triggers. Functional connectivity between the right hippocampus and right or left pallidum was strongly correlated to the NAA/Cho ratio in the right thalamus, suggesting neurochemical modulation of these brain areas through thalamic connections. To draw statistically significant conclusions a larger cohort is needed.
... Both striatal and pallidal compartments are then bidirectionally connected to the brainstem, but the organization of the descending pathways that connect these cerebral nuclei with the brainstem has been best portrayed for the dorsal striatum/dorsal pallidum, forming the well-known basal ganglia network (Fig. 5). Indeed, in addition to the hyperdirect pathway from the isocortex to the STN, the basal ganglia network is usually divided into direct and indirect pathways (Künzle, 1975;McGeorge and Faull, 1989;Graybiel et al., 1994;Parent and Hazrati, 1995a;Nambu et al., 2002;Graybiel, 2004;Gerfen and Bolam, 2016;Tecuapetla et al., 2016). The direct pathway involves several types of medium spiny neurons in the dorsal striatum that project in the internal part of the Table summarizing the parcellation of the telencephalon based on the nomenclature of the Allen Brain Atlas and Swanson (Allen Institute, 2004;Swanson, 2004) with a slight modification from Barbier et al. (2020; CEAm is adjoined to the PALc, see comments in Phillipson (1979). ...
The subthalamic nucleus (STN) is an essential component of the basal ganglia and has long been considered to be a part of the ventral thalamus. However, recent neurodevelopmental data indicated that this nucleus is of hypothalamic origin which is now commonly acknowledged. In this work, we aimed to verify whether the inclusion of the STN in the hypothalamus could influence the way we understand and conduct research on the organization of the whole ventral and posterior diencephalon. Developmental and neurochemical data indicate that the STN is part of a larger glutamatergic posterior hypothalamic region that includes the premammillary and mammillary nuclei. The main anatomical characteristic common to this region involves the convergent cortical and pallidal projections that it receives, which is based on the model of the hyperdirect and indirect pathways to the STN. This whole posterior hypothalamic region is then integrated into distinct functional networks that interact with the ventral mesencephalon to adjust behavior depending on external and internal contexts.Significance statementIn this work, we suggest that networks between the telencephalon, including cerebral cortex and basal nuclei, with the whole posterior hypothalamus, including the subthalamic nucleus, posterior lateral hypothalamic, premammillary and mammillary nuclei, are built along topographically organized pathways that parallel the hyperdirect and indirect pathways that are characteristic of the basal ganglia network. This suggests a high degree of organizational convergence between the basal ganglia and longitudinal hypothalamic networks to control the expression of behavioral responses adapted to external and internal cues.
... The demographic characteristics of the control and primary TTH groups are shown in Table 1. This total cohort included 10 males and 10 females, mean age 32.3 ± 9.3 years (range, 23-57), with 13.3 ± 3.9 years of formal education (range, [6][7][8][9][10][11][12][13][14][15][16][17][18][19], and a mean Montreal Cognitive Assessment Table 2. ...
Tension-type headache (TTH) is the most prevalent type of primary headache. Many studies have shown that the pathogenesis of primary headache is associated with fine structural or functional changes. However, these studies were mainly based on migraine. The present study aimed to investigate whether TTH patients show functional disturbances compared with healthy subjects. We used restingstate functional magnetic resonance imaging (fMRI) and regional homogeneity (ReHo) analysis to identify changes in the local synchronization of spontaneous activity in patients with TTH. Ten patients with TTH and 10 age-, gender-, and education-matched healthy controls participated in the study. After demographic and clinical characteristics were acquired, a 3.0-T MRI system was used to obtain resting-state fMRIs. Compared with healthy controls, the TTH group exhibited significantly lower ReHo values in the bilateral caudate nucleus, the precuneus, the putamen, the left middle frontal gyrus, and the superior frontal gyrus. There was no correlation between mean ReHo values in TTH patients and duration of TTH, number of attacks, duration of daily attacks, Visual Analogue Scale score, or Headache Impact Test-6 score. These results suggest that TTH patients exhibit reduced synchronization of neuronal activity in multiple regions involved in the integration and processing of pain signals.
... Organizzazione modulare del neostriato. A. Graybiel (2004) e Goldman-Rakic P. (2000) hanno dimostrato che le terminazioni delle afferenze striatali, derivanti dalla corteccia cerebrale oltre che dal talamo sono organizzate in moduli, analogamente alle colonne della corteccia cerebrale. Ricerche neurochimiche hanno confermato questo tipo di organizzazione, evidenziando la peculiare distribuzione a chiazze dei vari neurotrasmettitori e neuropeptidi come la dopamina, l'acetilcolina e la sostanza P. I compartimenti più minuscoli dei moduli striatali sono stati chiamati striosomi. ...
... The striatum is the main input structure of the basal ganglia, an ensemble of integrative subcortical nuclei enabling the elaboration of complex motor behavior (Bolam et al., 2000;Graybiel, 2004;Nicola, 2007;Gerfen and Surmeier, 2011). The GABAergic medium-sized spiny projections neurons (MSNs) that constitute the vast majority of striatal neurons (∼95% in rodents) integrate cortical and thalamic excitatory inputs and are modulated by dopaminergic inputs and striatal interneurons (Gerfen and Surmeier, 2011). ...
The striatum projection neurons are striatonigral and striatopallidal medium-sized spiny neurons (MSNs) that preferentially express D1 (D1R) and D2 (D2R) dopamine receptors, respectively. It is generally assumed that these neurons are physically intermingled, without cytoarchitectural organization although this has not been tested. To address this question we used BAC transgenic mice expressing enhanced green fluorescence (EGFP) under the control of Drd1a or Drd2 promoter and spatial point pattern statistics. We demonstrate that D1R- and D2R-expressing MSNs are randomly distributed in most of the dorsal striatum, whereas a specific region in the caudal striatum, adjacent to the GPe, lacks neurons expressing markers for indirect pathway neurons. This area comprises almost exclusively D1R-expressing MSNs. These neurons receive excitatory inputs from the primary auditory cortex and the medial geniculate thalamic nucleus and a rich dopamine innervation. This area contains cholinergic and GABAergic interneurons but apparently no D2R/A2aR modulation because no fluorescence was detected in the neuropil of Drd2-EGFP or Drd2-Cre, and Adora-Cre BAC transgenic mice crossed with reporter mice. This striatal area that expresses calbindin D28k, VGluT1 and 2, is poor in μ opiate receptors and preproenkephalin. Altogether, the differences observed in D1R-MSNs, D2R-MSNs, and interneurons densities, as well as the anatomical segregation of D1R- and D2R/A2aR-expressing MSNs suggest that there are regional differences in the organization of the striatum.
... Their activity appears to be unrelated to movements while they discharge phasically in response to sensory stimuli serving as a cue for reward delivery and consumption. 47 Moreover, thalamic projections to the striatum engage cholinergic interneurons to modulate corticostriatal inputs, thereby supporting their fundamental role in filtering excitatory afferents. 48 Cholinergic dysfunction must be important in dystonia considering that partially effective therapies for the disorder are anticholinergic drugs. ...
Work over the past 2 decades has led to substantial changes in our understanding of dystonia pathophysiology. Three general abnormalities appear to underlie the pathophysiological substrate. The first is a loss of inhibition. This makes sense considering that it may be responsible for the excess of movement and for the overflow phenomena seen in dystonia. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Third, evidence from animal models of dystonia as well as from patients with primary dystonia has revealed significant alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. We speculate that during motor learning this abnormal plasticity may lead to an abnormal sensorimotor integration, leading to consolidation of abnormal motor engrams. If so, then removing this abnormal plasticity might have little immediate effect on dystonic movements because bad motor memories have already been ''learned'' and are difficult to erase. These considerations might explain the delayed clinical effects of deep brain stimulation (DBS) in patients with generalized dystonia. Current lines of research will be discussed from a network perspective. © 2013 Movement Disorder Society.
... Damage to this loop in primates produces problems with motor and cognitive skills that require planning and manipulating patterns of sequences over time (Fuster, 1995). The striatum is also a major site for adaptive plasticity (Graybiel, 2004). ...
writing this chapter on an aging Sony notebook computer with a sticky Q key that I bought six years ago) is a linear sequence of words. But in order to extract the intended meaning, the reader must combine the words in just the right way. That much is obvious. What is not obvious is how we do that in real time, as we read or listen to a sentence (see Tanenhaus, this volume). The standard answer to that question, which derives from generative linguistic theories (Chomsky, 1986), is that we combine words at two levels: a level of structure (syntax) and a level of meaning (semantics). In our example sentence, syntactic combination entails assigning the grammatical subject role to I, the direct object role to this chapter, the object of the preposition role to aging Sony notebook computer, and so on. Semantic combination entails identifying who is doing the writing (the Agent) and what is being written (the Theme). Furthermore, the standard view claims that syntactic combination involves application of phrase structure rules that are abstracted away from individual words. For example, the rule S NP VP stipulates that every sentence in English is composed of a noun phrase and a verb phrase, in that order, regardless of the individual words in the sentence. relationships within each sentence, in which some phrases or clauses modify others (e. g., the prepositional phrase with a sticky Q key modifies the noun phrase aging Sony notebook computer). The phrase structure rules are also claimed to contain recursive elements that permit sentences
... Using interconnected closed or open neuronal loops with prefrontal, limbic, sensory and motor cortex, the basal ganglia network displays activity-dependent synaptic plasticity and coordinates action plans according to the motivation and motor information, and represents a neural substrate for procedural memory (revised in Graybiel, 2004;Kreitzer and Malenka, 2008;Haber and Calzavara, 2009;Pennartz et al., 2009). The dorsal striatum is especially involved in motor control while the ventral striatum, including nucleus accumbens (NAc), is mainly related to limbic and cognitive functions (Nicola, 2007). ...
... The learning rules used includes mechanisms for delayed reward so this can readily be incorporated. It could further be relevant to change the weight of the contributions from each pathway (Graybiel, 2004). Higher affinity of D2 receptors to low dopamine level compared to D1 receptors has been described (Jaber et al., 1997) which could suggest different learning rates or thresholds in the Go and the NoGo pathway. ...
Several studies have shown a strong involvement of the basal ganglia (BG) in action selection and dopamine dependent learning. The dopaminergic signal to striatum, the input stage of the BG, has been commonly described as coding a reward prediction error (RPE), i.e., the difference between the predicted and actual reward. The RPE has been hypothesized to be critical in the modulation of the synaptic plasticity in cortico-striatal synapses in the direct and indirect pathway. We developed an abstract computational model of the BG, with a dual pathway structure functionally corresponding to the direct and indirect pathways, and compared its behavior to biological data as well as other reinforcement learning models. The computations in our model are inspired by Bayesian inference, and the synaptic plasticity changes depend on a three factor Hebbian-Bayesian learning rule based on co-activation of pre- and post-synaptic units and on the value of the RPE. The model builds on a modified Actor-Critic architecture and implements the direct (Go) and the indirect (NoGo) pathway, as well as the reward prediction (RP) system, acting in a complementary fashion. We investigated the performance of the model system when different configurations of the Go, NoGo, and RP system were utilized, e.g., using only the Go, NoGo, or RP system, or combinations of those. Learning performance was investigated in several types of learning paradigms, such as learning-relearning, successive learning, stochastic learning, reversal learning and a two-choice task. The RPE and the activity of the model during learning were similar to monkey electrophysiological and behavioral data. Our results, however, show that there is not a unique best way to configure this BG model to handle well all the learning paradigms tested. We thus suggest that an agent might dynamically configure its action selection mode, possibly depending on task characteristics and also on how much time is available.
... The importance of basal ganglia (BG) networks for sequential motor control remains a topic of debate (Marsden, 1984;Mink, 1996). Several lines of research suggest that the motor circuit of the BG plays an important role in sequential behaviors (reviewed recently by Graybiel, 2004;Keele et al., 2003). One of the most prevalent hypotheses is that the BG contributes to the "proceduralization" of action sequences (Eichenbaum and Cohen, 2001). ...
... Synaptic plasticity in substantia nigra reticulata www.learnmem.org and tasks (Takakusaki et al. 2003Takakusaki et al. , 2004 Graybiel 2004 Graybiel , 2008; Yin and Knowlton 2006; Wickens 2009; Surmeier et al. 2011); they may be the port that allows one or the other to pass (Sarvestani et al. 2011 ), thus making action selection. Therefore, in agreement with the present experimental data, we would like to propose , as a first approximation, that each SNr neuron may act as a logical binary gate with two main inputs (seeTable 1): direct and indirect BG pathways. ...
There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral (direct pathway) synapses are not known. Here, we used electrophysiological techniques to describe dopamine D(1)-receptor-mediated facilitation in striatonigral synapses in the context of its interaction with glutamatergic inputs, probably coming from the subthalamic nucleus (STN) (indirect pathway) and describe a striatonigral cannabinoid-dependent long-term synaptic depression (LTD). It is shown that striatonigral afferents exhibit D(1)-receptor-mediated facilitation of synaptic transmission when NMDA receptors are inactive, a phenomenon that changes to cannabinoid-dependent LTD when NMDA receptors are active. This interaction makes SNr neurons become coincidence-detector switching ports: When inactive, NMDA receptors lead to a dopamine-dependent enhancement of direct pathway output, theoretically facilitating movement. When active, NMDA receptors result in LTD of the same synapses, thus decreasing movement. We propose that SNr neurons, working as logical gates, tune the motor system to establish a balance between both BG pathways, enabling the system to choose appropriate synergies for movement learning and postural support.
... Along with the GPi, the SNr represents the main output structure of the basal ganglia directly influencing the activity of thalamus and cortex at the end of motor program information processing108109110111. SNr neurons have a tonic firing discharge [112, 113] resulting from the inhibitory striatonigral GABAergic afferents [108-110, [114] nd the excitatory afferents form the STN115116117. ...
Several recent studies have emphasized a crucial role for the nitrergic system in movement control and the pathophysiology of the basal ganglia (BG). These observations are supported by anatomical evidence demonstrating the presence of nitric oxide synthase (NOS) in all the basal ganglia nuclei. In fact, nitrergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high expression of nitric oxide (NO)-producing neurons, with the striatum having the greatest number, together with important NO afferent input. In this paper, the distribution of NO in the BG nuclei will be described. Furthermore, evidence demonstrating the nitrergic control of BG activity will be reviewed. The new avenues that the increasing knowledge of NO in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. For example, inhibition of striatal NO/guanosine monophosphate signal pathway by phosphodiesterases seems to be effective in levodopa-induced dyskinesia. However, the results of experimental studies have to be interpreted with caution given the complexities of nitrergic signalling and the limitations of animal models. Nevertheless, the NO system represents a promising pharmacological intervention for treating Parkinson's disease and related disorders.
... Numerous imaging studies of migraine patients have described multiple changes in brain functions as a result of migraine attacks: these included enhanced cortical excitability [2], increased gray matter volume in some regions and decreased in others, [3,4]; enhanced brain blood flow567; and altered pain modulatory systems8910. The Basal Ganglia (BG) are a major site for adaptive plasticity in the brain, affecting in the normal state a broad range of behaviors [11] and neurological and psychiatric conditions [12] including pain [13,14]. The BG seem to be involved in the integration of information between cortical and thalamic regions and in particular the three domains of pain processing -sensory, emotional/cognitive and endogenous/modulatory. ...
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).
In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain.
Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.
... Any disruption to the delicate balance of this circuitry can therefore interrupt the intended motor output (Afifi 1994, Saint-Cyr et al. 1995. Diseases such as Huntington's disease, and Parkinson's disease (PD) are all movement related disorders that occur as a result of pathology within a specific input or output region of the basal ganglia (Hallett 1993, Bonnet and Hoveto 1999, McAuley 2003, Graybiel 2004. In part, this thesis will focus on investigating the pathophysiology within the oculomotor circuitry that occurs as a result of Parkinson's disease. ...
... The nervous system also has powerful cell-autonomous and cell-nonautonomous mechanisms to mitigate the effects of diseaseassociated mutations (Arrasate et al. 2004; Finkbeiner et al. 2006; Mitra et al. 2009; Palop et al. 2007). Indeed, some adaptive changes may contribute to symptoms under some circumstances (Graybiel 2004; Picconi et al. 2005). Finally, the use of symptoms to detect age of disease onset is somewhat arbitrary. ...
Huntington's disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neurodegeneration. The polyQ expansion makes Htt prone to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins tend to slow disease progression in HD models. This article will focus on HD and the evidence that it is a conformational disease.
... The putamen is one brain structure which exhibits particularly high neuroplasticity because of its elevated cortico-thalamic input and D2 receptor density (Graybiel, 2004;Hall et al., 1994). Both of these mediating factors may have contributed to the observed volumetric alterations, as childhood adversity is associated with dysfunctional cortico-thalamic pathways related to stress, reward and emotion processing (Dillon et al., 2009;Masten et al., 1999), and the presence of dopaminergic polymorphisms have been shown to affect D2 receptor expression (Duan et al., 2003). ...
Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.
... Chen and Hallett, 1999;Espay et al., 2006;Ridding et al., 1995;Rona et al., 1998). Ainsi, au cours des dystonies, il existerait une perte de l'inhibition exercée par le GABA dans les aires sensorimotrices(Hallett, 2011; L. M. Levy and Hallett, 2002).3.2 -Intégration sensorimotrice anormaleLes ganglions de la base jouent un rôle important dans l'intégration des informations sensorimotrices(Graybiel, 2004;Lovinger, 2010) (Abbruzzese et al., 2001Bara-Jimenez et al., 1998;Braun et al., 2003;Murase et al., 2000). Une défaillance dans la discrimination spatiale et temporelle des stimuli sensoriels a été reportée chez des patients présentant une dystonie focale, ou porteur d'une mutation génétique mais asymptomatiques(Braun et al., 2003;Scontrini et al., 2009;Tinazzi et al., 2009). ...
Introduction : La dystonie est définie comme un syndrome de cocontractions musculaires soutenues aboutissant à des mouvements répétitifs et des postures anormales. Cependant la physiopathologie des dystonies reste mal comprise. Les études menées chez l’homme soulignent le rôle crucial des ganglions de la base dans la physiopathologie des dystonies. Des données récentes obtenues chez le rongeur suggèrent l’implication d’un désordre de la transmission cholinergique striatale mais es modèles qu’ils soient génétiques ou pharmacologiques n’aboutissent pas toujours à un phénotype de dystonie. C’est pourquoi il était important de proposer une étude chez le primate non humain, visant à vérifier notre hypothèse de travail, à savoir : est-ce qu’une augmentation de la transmission cholinergique dans le putamen est capable d’induire un phénotype clinique de dystonie similaire à celui rencontré chez l’homme.Méthodes : Nous avons réalisé des infusions chroniques d’un agoniste muscarinique non sélectif (Oxotremorine) au sein du territoire sensori-moteur du striatum chez le primate non-humain. Les symptômes cliniques induits par ce produit ont été évalués à l’aide de l’échelle de Burke-Fahn-Marsden (BFM) adaptée à l’animal. Nous avons également utilisé une approche électromyographique pour caractériser l’activité musculaire en lien avec la clinique ainsi que des enregistrements de l’activité Multi-Unitaire et Unitaire au sein des ganglions de la base afin d’établir des corrélations électro-cliniques.Résultats : Les infusions d’Oxotremorine nous ont permis d’observer : (i) des postures et des mouvements anormaux similaires aux mouvements dystoniques rencontrés en pathologie humaine ; (ii) une fréquence de décharge neuronale anormalement basse dans le GPi (13,5Hz) et un pattern de décharge de type « bursty » principalement lorsque les symptômes sont sévères ; (iii) une activité oscillatoire (28-30Hz) au sein du putamen, du GPe et du GPi; (iv) l’absence de cohérence de l’activité oscillatoire entre ces structures ; (v) que le GPi est la seule structure à présenter une cohérence de l’activité oscillatoire.Conclusion : Nos travaux démontrent pour la première fois qu’un modèle de dystonie chronique peut être obtenu chez le primate non humain par augmentation du tonus cholinergique dans le putamen. Ce travail valide l’hypothèse de l’implication des interneurones cholinergiques dans la physiopathologie des dystonies. Ils confortent l’idée qu’une augmentation du tonus cholinergique peu à elle seule induire un phénotype de dystonie.
... 3. Long-term potentiation: New learning is ultimately encoded through enhancement of relevant synapses so as to form new neural networks or enhance or extend old ones (Quirk & Mueller, 2008). This is how new content is added to the mind's repertoire, affecting any of the three steps from appraisal, to core emotional activation and motivation, and, finally, to reaction (Graybiel, 2004). New learning, while notably also operating to avoid negative affective states, allows for different and more adaptive AFFECT AVOIDANCE MODEL 27 behavioral response patterns in response to stress beyond pre-existing misapplied "adaptations" to stress. ...
The field of psychotherapy integration has long sought an explanatory model for therapeutic action across orientations. We take advantage of advances in the neurobiology of memory and emotion to propose such a model for psychopathology and its treatment. These pathologies are generated by the brain’s evolutionally architected systems for prediction and mitigation of danger and are triggered by core emotional circuits. Although generally avoidance of negative core emotion is adaptive as a mechanism of coping with threat, this same process may lead to the entrenched dysfunctional patterns that comprise psychopathology. Avoidance of predicted negative core emotion is proposed as a mechanism of resistance to therapeutic change in that the aim of psychotherapy is appraised as potential loss of important protections. Psychotherapy makes use of five mechanisms to produce lasting change in these maladaptive patterns: extinction, reconsolidation, new learning, arousal regulation, and motivation for change. These are mapped to six universal aims of psychotherapy: Building and maintaining a positive therapeutic relationship, activating relevant emotions, exposing the patient/client to new information, challenging maladaptive cognition, fostering voluntary behavior change, and developing a new narrative. By establishing links extending from actions taken by therapists to neurophysiological change mechanisms, the Affect Avoidance Model provides a unifying explanation of psychopathology and an integrative view of therapeutic technique and action.
... Ainsi, la majeure partie des projections des différents territoires fonctionnels corticaux (limbiques, associatifs, sensori-moteur) va projeter sur des territoires fonctionnels spécifiques au niveau du striatum (putamen, noyau caudé, nucleus accumbens), cette ségrégation territoriale va se maintenir au sein de la circuiterie interne des BG. Les informations de sorties seront ainsi transmises aux cortex via des noyaux relais thalamiques appropriés(98).Un rôle important du striatum pourrait être d'optimiser le comportement en affinant la sélection des actions en fonction du contexte et ainsi façonner les habitudes et les compétences spécifiques en modulant les différents répertoires moteurs, cognitifs et émotionnels(99)(100)(101).Il pourrait effectuer le tri des informations fournies par le cortex et le thalamus afin de faciliter la sélection d'une action appropriée parmi un ensemble depossibilités(102,103). Ainsi, les différentes parties du striatum semblent être impliquées dans différents aspects de l'apprentissage procédural. Le noyau caudé, en lien avec le cortex préfrontal dorsolatéral contribue au comportement par la sélection de schémas d'action corrects et de sous-objectifs appropriés basés sur l'évaluation des conséquences de l'action.Le putamen, de concert avec les cortex moteurs, semble soutenir quant à lui les fonctions sensorimotrices limitées à l'apprentissage des routines comportementales, tandis que le striatum ventral (noyau accumbens), à travers ses rapports avec le cortex orbito frontal, est engagé dans les aspects motivationnels et affectifs du comportement(104,105). ...
Contexte : […], le mode d'interaction entre les signaux corticaux et striataux reste flou. Dans la présente thèse, nous avons d’abord saisi l’opportunité d’enregistrements stéréoélectroencéphalographiques chez des patients atteints d’épilepsie pharamcorésistante pour analyser qualitativement et quantitativement l’activité ictale du striatum. Deuxièmement, nous avons créé un modèle primate de crises motrices focales sous-corticales induites par des injections striatales antagonistes GABAergiques. Première étude : Patients et méthode : onze patients ayant subi une évaluation SEEG ont été inclus prospectivement s'ils remplissaient deux critères d'inclusion: i) au moins un contact explorait le striatum, ii) au moins deux crises avaient été enregistrées. Les régions d'intérêt corticales et sous-corticales ont été définies et différentes périodes d'intérêt ont été analysées. Les signaux SEEG ont été inspectés visuellement et une analyse de corrélation non linéaire h2 a été réalisée pour étudier la connectivité fonctionnelle entre les régions corticales d’intérêt et le striatum. Résultats : Deux patterns principaux d'activation striatale ont été enregistrés : le plus fréquent était caractérisé par une activité alpha / bêta précoce débutant dans les cinq premières secondes suivant le début de la crise. Le second était caractérisé par une activité thêta / delta tardive plus lente. Une différence significative des indices de corrélation h2 a été observée au cours de la période préictale et début de crise par rapport au tracé de fond pour l'indice striatal global, l'indice mésio-temporal / striatal, l'index latérotemporal / striatal, l'index insulaire / striatal, l'index préfrontal / striatal. En outre, une différence significative des indices de corrélation h2 a été observée pendant la période de fin de crise par rapport à toutes les autres périodes d’intérêt. Deuxième étude : Matériel et méthode : Des injections antagonistes aiguës de GABAergic (bicuculline) ont été réalisées sur trois Macaca fascicularis dans la partie sensorimotrice du striatum. Les modifications comportementales ont été enregistrées et scorées selon une échelle de Racine modifiée. L'électromyographie, l'électroencéphalographie, les potentiels de champ locaux des noyaux gris centraux ont été enregistrés au cours de chaque expérience. Une analyse de retromoyenage a été effectuée pour chaque session enregistrée. Résultats: sur les 39 injections de bicuculline, 29 (74,3%) ont produit des changements comportementaux reproductibles caractérisés par des secousses myocloniques répétitives et pseudopériodiques avec des crises tonico-cloniques généralisées. Les injections de NaCl n'ont jamais entraîné de changement de comportement. Les secousses myocloniques étaient clairement détectables sur le signal EMG sous la forme d'une courte bouffée stéréotypée concomitante de pointes épileptiques anormales enregistrées sur l'EEG. Une analyse de rétromoyennage à partir des myoclonies EMG a montré que l'activité électrophysiologique commençait significativement plus tôt dans le striatum (p <0,0001), le GPe (p <0,0003) et le GPi (p <0,0086) que dans le cortex. Conclusion : Ces modifications du niveau de synchronisation entre les activités corticales et striatales pourraient s’inscrire dans un mécanisme endogène contrôlant la durée des oscillations anormales au sein de la boucle striato-thalamo-corticale et, de fait leur terminaison. Les interneurones GABAergic de type fast-spiking pourraient jouer un rôle crucial dans la synchronisation du réseau cortico-striato-thalamique et une modification GABAergique brutale du striatum peut provoquer une crise focale. Le rôle joué par les noyaux gris centraux dans le renforcement des mécanismes sous-jacents à la cessation de la propagation ictale devrait inspirer de nouveaux schémas de stimulation cérébrale profonde chez les patients atteints d'épilepsies focales pharmacorésistantes non chirurgicales.
... It has been suggested that sensorimotor integration plays a major role in the pathophysiology of dystonia (3). The basal ganglia are thought to have a role in the modulation of sensory stimuli and a direct impact on somatosensory integration (34)(35)(36). Furthermore, the cerebellum receives input from the spinal cord and interacts with the somatosensory system (37,38). ...
Abnormalities in the somatosensory system are increasingly being recognized in patients with dystonia. The aim of this study was to investigate whether sensory abnormalities are confined to the dystonic body segments or whether there is a wider involvement in patients with idiopathic dystonia. For this purpose, we recruited 20 patients, 8 had generalized, 5 had segmental dystonia with upper extremity involvement, and 7 had cervical dystonia. In total, there were 13 patients with upper extremity involvement. We used Quantitative Sensory Testing (QST) at the back of the hand in all patients and at the shoulder in patients with cervical dystonia. The main finding on the hand QST was impaired cold detection threshold (CDT), dynamic mechanical allodynia (DMA), and thermal sensory limen (TSL). The alterations were present on both hands, but more pronounced on the side more affected with dystonia. Patients with cervical dystonia showed a reduced CDT and hot detection threshold (HDT), enhanced TSL and DMA at the back of the hand, whereas the shoulder QST only revealed increased cold pain threshold and DMA. In summary, QST clearly shows distinct sensory abnormalities in patients with idiopathic dystonia, which may also manifest in body regions without evident dystonia. Further studies with larger groups of dystonia patients are needed to prove the consistency of these findings.
... The available literature suggests that antagonism at 5-HT 2C Rs might have beneficial effects on TLE patients, while their activation shows a clear anti-absence effect. These paradoxical anticonvulsant efficacy of 5-HT 2C R antagonists and agonists can be reconciled, taking into consideration that i) the two types of epilepsy have a different network substrate, ii) both agonism and antagonism induce 5-HT 2C R desensitization or downregulation (Graybiel, 2004), and/or iii) the existence of different populations of 5-HT 2C Rs with different signal transduction mechanisms. Moreover, the anti-versus pro-epileptic effects of the 5-HT 2C R activation might depend on the dose of the ligands used, with a pro-convulsive effects being present when the receptors are excessively activated. ...
... Cognition involves numerous cortical loops through the basal ganglia that involve the prefrontal association cortex and limbic cortex. The basal ganglia (BG) help transform sensory input and cognitive processes into behavior [26]. In white matter, maturation changes are related to ongoing myelination. ...
Longitudinal magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies reveal significant changes in brain structure and structural networks that occur together with cognitive and behavioral maturation in childhood. However, the underlying cellular changes accompanying brain maturation are less understood. Examining regional age-related changes in metabolite levels provides insight into the physiology of neurodevelopment. Magnetic resonance spectroscopy (MRS) measures localize brain metabolism. The majority of neuroimaging studies of healthy development are from the developed world. In a longitudinal MRS study of 64 South African children aged 5 to 10 years old (29 female; 29 HIV exposed, uninfected), we examined the age-related trajectories of creatine (Cr+PCr), N-acetyl-aspartate (NAA), the combined NAA+N-acetyl-aspartyl-glutamate (NAAG), choline (GPC+PCh), glutamate (Glu) and the combined Glu+glutamine (Glu+Gln) in voxels within gray and white matter, as well as subcortically in the basal ganglia (BG). In frontal gray matter, we found age-related increases in Cr+PCr, NAA, NAA+NAAG and Glu+Gln levels pointing to synaptic activity likely related to learning. In the BG we observed increased levels of Glu, Glu+Gln and NAA+NAAG with age that point to subcortical synaptic reorganization. In white matter, we found increased levels of Cr+PCr, NAA, NAA+NAAG, Glu and Glu+Gln with age, implicating these metabolites in ongoing myelination. We observed no sex-age or HIV exposure-age interactions, indicating that physiological changes are independent of sex during this time period. The metabolite trajectories presented, therefore, provide a critical benchmark of normal cellular growth for a low socioeconomic pediatric population in the developing world against which pathology and abnormal development may be compared.
... On that basis, the selective activation of afferent pathways could be viewed as an attractive way to promote neuroplasticity in specific brain areas by simply modulating the stimulation parameters. For example, the specific activation of basal ganglia during CONV might be relevant for minimizing proprioceptive deficits in elderly individuals 62 or in patients suffering from movement disorders such as Parkinson's and Huntington's disease 64,65 . However, our results cannot yet be translated into clinical applications and personalized rehabilitation since only young and healthy individuals were tested. ...
The influence of neuromuscular electrical stimulation (NMES) parameters on brain activation has been scarcely investigated. We aimed at comparing two frequently used NMES protocols - designed to vary in the extent of sensory input. Whole-brain functional magnetic resonance imaging was performed in sixteen healthy subjects during wide-pulse high-frequency (WPHF, 100 Hz–1 ms) and conventional (CONV, 25 Hz–0.05 ms) NMES applied over the triceps surae. Each protocol included 20 isometric contractions performed at 10% of maximal force. Voluntary plantar flexions (VOL) were performed as control trial. Mean force was not different among the three protocols, however, total current charge was higher for WPHF than for CONV. All protocols elicited significant activations of the sensorimotor network, cerebellum and thalamus. WPHF resulted in lower deactivation in the secondary somatosensory cortex and precuneus. Bilateral thalami and caudate nuclei were hyperactivated for CONV. The modulation of the NMES parameters resulted in differently activated/deactivated regions related to total current charge of the stimulation but not to mean force. By targeting different cerebral brain regions, the two NMES protocols might allow for individually-designed rehabilitation training in patients who can no longer execute voluntary movements.
... Basal ganglia circuits transform activity in the cerebral cortex to control motor learning, habit formation, and action selection based on desirable outcomes (Balleine et al., 2007;Cisek and Kalaska, 2010;Graybiel, 2004;Hikosaka et al., 2000;Mink, 1996;Wichmann and DeLong, 2003;Yin and Knowlton, 2006). These effects on behavior are mediated by two parallel striatal circuits involving two subtypes of medium spiny neurons (MSN): the direct pathway neurons that express the dopamine D1 receptor (D1-MSN), and the indirect pathway neurons that express the dopamine D2 receptor (D2-MSN) (Gerfen et al., 1990). ...
An influential striatal model postulates that neural activities in the striatal direct and indirect pathways promote and inhibit movement, respectively. Normal behavior requires coordinated activity in the direct pathway to facilitate intended locomotion and indirect pathway to inhibit unwanted locomotion. In this striatal model, neuronal population activity is assumed to encode locomotion relevant information. Here, we propose a novel encoding mechanism for the dorsal striatum. We identified spatially compact neural clusters in both the direct and indirect pathways. Detailed characterization revealed similar cluster organization between the direct and indirect pathways, and cluster activities from both pathways were correlated with mouse locomotion velocities. Using machine-learning algorithms, cluster activities could be used to decode locomotion relevant behavioral states and locomotion velocity. We propose that neural clusters in the dorsal striatum encode locomotion relevant information and that coordinated activities of direct and indirect pathway neural clusters are required for normal striatal controlled behavior.
... This topographic pattern of innervation of the CEAc,l is reminiscent of the cortical projections that innervate distinct band-shaped domains within the caudoputamen nucleus, but each of these domains receives convergent inputs from several distinct cortical areas. This arrangement in the structural organization of connections between the cortex and striatum was interpreted by Graybiel as important for learning and may play a role in habit acquisition (49)(50)(51)(52). From a single injection site in the INS, striatal projections involved parts of the caudoputamen and ventral striatum, including the nucleus accumbens and olfactory tubercle, each at the origin of distinct branches of the basal ganglia network, therefore implying the multiple processes related to motor, motivation, and cognitive responses initiated from the INS. ...
The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop “no-eat” signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.
... The basal ganglia receive the evoked potential of the cerebral cortex and pass through the efferent projection fibers to form the basal ganglion circuit, which is then returned to the cerebral cortex by the thalamus (Graybiel, 2004). Through this neural circuit, the basal ganglia coordinate the regulation of the body, limbic system, and prefrontal function. ...
Background
Previous positron emission tomography studies have reported the changes of cerebral glucose metabolism in bipolar disorder. However, the findings across studies remain controversial, containing differing results.
Methods
A systematic literature search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted. We conducted a voxel‐wide meta‐analysis of cerebral glucose metabolism studies, using the seed‐based mapping approach, in patients with bipolar disorder (BD).
Results
We identified 7 studies suitable for inclusion, which included a total of 126 individuals with BD and 160 healthy controls. The most consistent and robust findings were an increase in cerebral glucose metabolism in the right precentral gyrus and a decrease in the left superior temporal gyrus, left middle temporal gyrus, and cerebellum. Additionally, the sex distribution and illness duration had significant moderating effects on cerebral glucose metabolism alterations.
Conclusions
Cerebral glucose metabolism alterations in these brain regions are likely to reflect the disease‐related functional abnormalities such as emotion and cognition. These findings contribute to a better understanding of the neurobiological underpinnings of bipolar disorder.
Limitations.
This study was done at a study level and cannot be addressed at the patient level. Subgroup analysis of BD I and BD II is not possible due to limited literature data.
... We found that fALFF values of the left caudate, left putamen, the right dorsolateral superior frontal gyrus, and the right medial superior frontal gyrus in the iPSCI group were lower than those in the HC group. The caudate and putamen belong to the striatum, the largest input nucleus to the basal ganglia, and receive a large input from the neocortex and thalamus (Graybiel, 2004). According to the current knowledge on basal ganglia circuits, cortico-basal ganglia circuits carry motor information and cognitive function (Milardi et al., 2019). ...
Stroke causes alterations in local spontaneous neuronal activity and related networks functional connectivity. We hypothesized that these changes occur in patients with post-stroke cognitive impairment (PSCI). Fractional amplitude of low-frequency fluctuations (fALFF) was calculated in 36 patients with cognitive impairment, including 16 patients with hemorrhagic stroke (hPSCI group), 20 patients with ischemic stroke (iPSCI group). Twenty healthy volunteers closely matched to the patient groups with respect to age and gender were selected as the healthy control group (HC group). Regions with significant alteration were regarded as regions of interest (ROIs) using the one-way analysis of variance, and then the seed-based functional connectivity (FC) with other regions in the brain was analyzed. Pearson correlation analyses were performed to investigate the correlation between functional indexes and cognitive performance in patients with PSCI. Our results showed that fALFF values of bilateral posterior cingulate cortex (PCC)/precuneus and bilateral anterior cingulate cortex in the hPSCI group were lower than those in the HC group. Compared with the HC group, fALFF values were lower in the superior frontal gyrus and basal ganglia in the iPSCI group. Correlation analysis showed that the fALFF value of left PCC was positively correlated with MMSE scores and MoCA scores in hPSCI. Besides, the reduction of seed-based FC values was reported, especially in regions of the default-mode network (DMN) and the salience network (SN). Abnormalities of spontaneous brain activity and functional connectivity are observed in PSCI patients. The decreased fALFF and FC values in DMN of patients with hemorrhagic and SN of patients with ischemic stroke may be the pathological mechanism of cognitive impairment. Besides, we showed how to use fALFF values and functional connectivity maps to specify a target map on the cortical surface for repetitive transcranial magnetic stimulation (rTMS).
By whatever technique used to facilitate the process, most therapy in a clinical setting consists of taking a previously learned set of maladaptive beliefs and behaviors and replacing them with newly learned adaptive beliefs and behaviors. Even therapeutic techniques that do not focus directly on behavior change can be understood in terms of implied change. The principles of learning are reviewed.
Basal ganglia are engaged in seizure propagation, control of seizures, and in epilepsy-induced neuroplasticity. Here, we tested the hypothesis that previously observed histological and neurochemical changes in the striatum of amygdala-kindled rats as a model of temporal lobe epilepsy are reflected in alterations of spontaneous striatal firing rates and patterns. Because experimental histological and clinical imaging studies indicated a bilateral involvement of the striatum in epilepsy-induced neuroplasticity, in vivo single-unit recordings were done bilaterally 1 day after a kindled seizure in rats kindled via the right amygdala.Compared to control animals, we observed (1) an increased irregularity of firing of neurons classified as striatal projection neurons and located in the anterior striatum ipsilateral to the kindling side and (2) an increased spontaneous activity of neurons classified as striatal projection neurons and located in the anterior striatum contralateral to the kindling side. These hyperactive neurons were located within the dorsolateral (sensorimotor) subregion of the striatum.The present study represents the first evidence of kindling-induced bilateral changes in electrophysiological properties of striatal neurons and demonstrates that the striatum is strongly affected by the functional reorganization of neurocircuits associated with kindling.The changes are probably caused by a combination of several factors including disturbed bilateral limbic and neocortical input as well as disturbed intrastriatal GABAergic function. The changes reflect a pathophysiological state predisposing the brain to epileptic discharge propagation or else (contralateral striatum) could represent a compensatory network of inhibitory circuits activated to prevent the propagation of seizure activity. The findings are relevant for a better understanding of kindling-induced network changes and might provide new targets for therapeutic manipulations in epilepsies.
Therapeutic agents and drugs of abuse regulate the extracellular signal-regulated kinase (ERK) cascade signaling in the medium-sized spiny neurons (MSNs) of the striatum. However, whether this regulation is associated with specific cortical and thalamic inputs has never been studied. We used Drd2-EGFP BAC-transgenic mice to undertake a topographical and cell-type specific analysis of ERK phosphorylation and two of its downstream targets histone H3 and ribosomal protein S6 (rS6) in the dorsal striatum following injection of SKF81297 (D1R-like agonist), quinpirole (D2R-like agonist) or apomorphine (non selective DA receptor agonist). In striatal areas receiving inputs from the cingulate/prelimbic, visual and auditory cortex, SKF81297 treatment increased phosphorylation of ERK, histone H3 and rS6 selectively in EGFP-negative MSNs of Drd2-EGFP mice. In contrast, no regulation was found in striatal region predominantly targeted by the sensorimotor and motor cortex. Apomorphine slightly enhanced ERK and rS6, but not histone H3 phosphorylation. This regulation occurred exclusively in EGFP-negative neurons mostly in striatal sectors receiving connections from the insular, visual and auditory cortex. Quinpirole administration inhibited basal ERK activation but did not change histone H3 and rS6 phosphorylation throughout the rostrocaudal axis of the dorsal striatum. This anatomo-functional study indicates that D1R and D2R agonists produce a unique topography and cell-type specific regulation of the ERK cascade signaling in the mouse striatum, and that those patterns are closely associated with particular cortical and thalamic inputs. This work evidences the need of a precise identification of the striatal areas under study to further understand striatal plasticity.
The basal ganglia are traditionally viewed as key components of the “extrapyramidal motor circuitry.” However, it has become clear over the past several decades that the influence of basal ganglia extends far beyond the motor system. Through its inputs from associative, limbic, and sensorimotor cortices, the striatum represents the main entrance for extrinsic information to the basal ganglia. Once integrated and processed at the striatal level, the information is conveyed to the pallidum and thence to thalamic or brainstem regions through segregated loops of information that gain access to motor and non-motor frontal cortical areas or descending reticular systems. Although basal ganglia disorders are commonly seen as motor deficits, it is now well established that the symptomatology and pathophysiology of disorders such as Parkinson's disease also comprise significant cognitive and emotional components. This chapter reviews the main anatomic features of the primate basal ganglia with particular emphasis on cellular microcircuits and neural networks that underlie some of the non-motor functions and dysfunctions of these brain regions in normal and diseased states.
This chapter reviews evidence for the multiple parallel memory systems hypothesis: the idea that different kinds of information are processed and stored in anatomically distinct brain systems. The historical development of evidence that several different kinds of information are learned and are selectively affected by damage to different brain areas is reviewed. Current evidence is described for the existence of memory for three different kinds of information that are processed and stored in three different, independently functioning neural systems in rats and humans. Evidence for cooperation and competition among the systems for control of behavior suggests that they function independently and in parallel.
L’insieme dei gangli della base (GB) costituisce un sistema (o sistemi) così complesso che è stato definito, parafrasando
Winston Churchill, “un indovinello avvolto nel mistero, dentro un enigma”.
Exercise-induced fatigue is a complex phenomenon involving the central nervous system (CNS) and muscle. In CNS, striatum is one of the key basal ganglia components which controls planning and execution of motor behaviors. The purpose of this study was to determine the influence of exercise-induced fatigue on striatum neuron's excitability. 56 rats were divided into control group (CG) and fatigue group (FG).10-day load- increasing swimming method was used to set up exercise-induced fatigue animal model. Rats' body weight and chemical indexes (CK&BU) were monitored. Extra cellular microelectrode recording technique in vivo was used to record striatum neurons spontaneous firing. In CG, high discharge frequency neuron's percentage is only 6% while in FG it increased to 19% (P
Abstract In order to reveal the effectof nigrostriatal dopamine system on action selection, first a computational model of the cortex-basal ganglia-thalamus loop is proposed and based on this model a simple compound,model realizing the Stroop effect is established. Even though Stroop task is mostly used to examine selective attention, the main objective of this work is to investigate the effect of action selection on Stroop task. The computational model of the cortex-basal ganglia-thalamusloop is a non-linear dynamical system which is not only capable of revealing the action selection property of basal ganglia but also capable of modelling the effect of dopamine on action selection. While the interpretation of action selection is based on the solutions of the non-linear dynamical system, the effect of dopamine is modelled by a parameter of the model. The inhibiting effect of dopamine on the habitual behaviour which corresponds to word reading in Stroop task and letting the novel one occur corresponding to colour naming is investigated using the compound,computational model established in this work. Keywords: computational modelling, action selection, basal ganglia, dopamine, Stroop task, non-linear dynamical system, bifurcations, domain of attraction. List of Symbols and Abbreviations: AI,artificial intelligence
Songbird vocal learning depends on the anterior forebrain pathway, the organization of which reflects a conserved vertebrate cortico-basal ganglia-thalamocortical loop architecture. We review the involvement of FoxP2 in this circuit, as well as FoxP1 and Cntnap2, both posited to participate alongside FoxP2. In the avian striatum, FoxP2 expression is regulated by singing, highlighting the possibility that developmental verbal dyspraxia arising from human FOXP2 mutation might primarily reflect a deficit in ongoing neural signaling, rather than developmental miswiring. We explore genes co-regulated with FoxP2 during singing and propose that Wnt trafficking and p63 signaling pathways may be crucial to speech and language. © 2013 Springer Science+Business Media New York. All rights are reserved.
5-Hydroxytryptamine 2A receptors (5-HT2ARs), have been implicated in various psychiatric and neurological disorders, including epilepsy. Interestingly, epileptic patients commonly present comorbid psychiatric symptoms, and a bidirectional link between depression and epilepsy has been suggested. Therefore, the alteration of 5-HT2A signalling might represent a common anatomical and neurobiological substrate of both pathologies. After a brief presentation of the role of 5-HT in epilepsy, this chapter illustrates how 5-HT2A receptors may directly or indirectly control neuronal excitability in networks involved in different types of epilepsy. It also synthetizes the preclinical and clinical evidence, demonstrating the role of these receptors in antiepileptic responses.
Recent theoretical work on the transmission of cultural behavior has focused on how and why information is transmitted. Less work has been done on the particular behaviors being transmitted. Here, I argue that the kind of behavior being transmitted can have a greater effect on the conservation of behavior than how or why the behavior was transmitted. Specifically, behaviors such as motor skills and habits, which are stored in nondeclarative memory, are more likely to be conservatively maintained over longer periods of time than declarative memories, which include easily changeable ideas and plans. Thus, behaviors, as manifested in artifact traits, are more or less likely to be maintained over time depending on where in the memory systems they are remembered. In sum, not all artifact traits have equivalent value when interpreting the spatial and temporal distribution of artifact traits.
Compulsivity and impulsivity are cross-cutting, dimensional symptom domains that span traditional diagnostic boundaries. We examine compulsivity and impulsivity from several perspectives and present implications for these symptom domains as they relate to classification. We describe compulsivity and impulsivity as general concepts, from the perspectives of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) Research Planning Agenda, and from the DSM-5 workgroups, literature reviews, and field trials. Finally, we detail alternative modes of classification for compulsivity and impulsivity in line with the Research Domain Criteria (RDoC) and International Classification of Diseases (ICD-11).
Functional connectivity (FC) has been used to investigate the pathophysiology of migraine. We aimed to identify atypical FC between the periaqueductal gray (PAG) and other brain areas in rats induced by repeated meningeal nociception. The rat model was established by infusing an inflammatory soup (IS) through supradural catheters in conscious rats. Quiescent and face-grooming behaviors were observed to assess nociceptive behavior. FC analysis seeded on the PAG was performed on rats 21 days after IS infusion. The rats exhibited nociceptive behavior correlates of human behaviors associated with migraine after IS infusion. The PAG showed increased FC with the prefrontal cortex, cingulate gyrus, and motor cortex but decreased FC with the basal ganglia, dorsal lateral thalamus, internal capsule and prelimbic cortex in the rat model. The atypical FC of the PAG with brain regions in the rat model that are involved in nociception, somatosensory processing, emotional processing, and pain modulation are consistent with the clinical data from migraineurs, indicate that resting-state FC changes in migraine patients may be a consequence of headache attacks, and further validate this rat model of chronic migraine.
Sforzandomi di renderne omogenei e coerenti approfondimento e descrizione, ho trattato argomenti di neuro-anatomia, neuro fisiologia e neuro biologia regionale. Conciliare materie complesse e vaste è di per sé molto arduo. Nuove teorie sul funzionamento della mente umana e sulle capacità di apprendimento dei primati e dei mammiferi in genere si susseguono, in particolare in anni recenti con ritmo incessante. Diventa difficile seguirne le numerose tesi e provare a compiere una esauriente sintesi che sia di base a nuovi, originali e personali approcci di studio. Divergenti sono le recenti scoperte di neurofisiologia. Alcune paragonano il funzionamento cerebrale ad un computer, sia pur sofisticato. Altre collegano la struttura del cervello alla complessità dei frattali, al limite tra Chaos quantistico e ordine assoluto. In questa ricerca, ho riportato teorie molto controverse sul comportamento umano ed animale ed ho approfondito le più recenti tesi che affiancano le leggi della termodinamica alle funzioni cerebrali fisiologiche e patologiche. Infine, ho aggiunto alcune nozioni riferite alle teorie degli insiemi numerici e geometrici nel descrivere particolari del comportamento motorio di difficile collocazione. Ho diviso la trattazione in nove capitoli principali, alcuni dei quali suddivisi in paragrafi, indicati questi ultimi con le lettere minuscole dell'alfabeto. I capitoli che costituiscono questa ricerca scientifica sono così titolati: 1. Processi mentali ed apprendimento.
This article explores the limits to conceptual integration between evolutionary biology, cognitive neuroscience and economics.
The new learning in the natural sciences supplies material to update and enrich the microfoundations of institutional economics—specifically,
the instinct–habit psychology. The framing of social reality with evolutionary concepts is, however, misguided in important
respects. Metaphorical modelling is the transfer of concepts developed for the understanding of one domain to another, ontological
distinct domain. The argument is made that the generalisation of Darwinian principles to the phenomena of institutional persistence
and change is theorising by metaphor, because there are crucial ontological differences separating the natural and social
domains. Social reality has the property of transmutability—meaning the social environment, unlike the natural domain, is changeable by human agency. This article endeavours to explain
how the generalisation of the natural selection principle evokes a fallacious conception of institutional reality. The idea
that ‘fitness’ in the social/economic sphere is a matter of purposive adaptation by agents to exogenous conditions is misleading, because real success in business or politics is transformative and is achieved by catalysing and
maintaining advantageous shifts of widely prevalent habits of thought and behaviour.
The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum.
Migraine is one of the most prevalent neurological disorders which is suggested to be associated with dysfunctions of the central nervous system. The purpose of the present study was to detect the altered functional connectivity architecture in the large-scale network of the whole brain in migraine without aura (MWoA). Meanwhile, the brain functional hubs which are targeted by MWoA could be identified. A new voxel-based method named functional connectivity density (FCD) mapping was applied to resting-state functional magnetic resonance imaging data of 55 female MWoA patients and 44 age-matched female healthy controls (HC). Comparing to HC, MWoA patients showed abnormal short-range FCD values in bilateral hippocampus, bilateral insula, right amygdale, right anterior cingulate cortex, bilateral putamen, bilateral caudate nucleus and the prefrontal cortex. The results suggested decreased intraregional connectivity of these pain-related brain regions in female MWoA. In addition, short-range FCD values in left prefrontal cortex, putamen and caudate nucleus were significantly negatively correlated with duration of disease in MWoA group, implying the repeated migraine attacks over time may consistently affect the resting-state functional connectivity architecture of these brain hubs. Our findings revealed the dysfunction of brain hubs in female MWoA, and suggested the left prefrontal cortex, putamen and caudate nucleus served as sensitive neuroimaging markers for reflecting the disease duration of female MWoA. This may provide us new insights into the changes in the organization of the large-scale brain network in MWoA.
The degree of parallel processing in frontal cortex-basal ganglia circuits is a central and debated issue in research on the basal ganglia. To approach this issue directly, we analyzed and compared the corticostriatal projections of two principal oculomotor areas of the frontal lobes, the frontal eye field (FEF) and the supplementary eye field (SEF). We first identified cortical regions within or adjacent to each eye field by microstimulation in macaque monkeys and then injected each site with either 35S-methionine or WGA-HRP conjugate. We analyzed the corticostriatal projections and also the interconnections of the pairs of cortical areas. We observed major convergence of the projections of the FEF and the SEF within the striatum, principally in the caudate nucleus. In cross sections through the striatum, both projections were broken into a series of discontinuous input zones that seemed to be part of complex three-dimensional labyrinths. Where the FEF and SEF projection fields were both present, they overlapped patch for patch. Thus, both inputs were dispersed within the striatum but converged with one another. Striatal afferents from cortex adjacent to the FEF and the SEF did not show convergence with SEF and FEF inputs, but did, in part, converge with one another. For all pairs of cortical areas tested, the degree of overlap in the corticostriatal projections appeared to be directly correlated with the degree of cortical interconnectivity of the areas injected. All of the corticostriatal fiber projections observed primarily avoided immunohistochemically identified striosomes. We conclude that there is convergence of oculomotor information from two distinct regions of the frontal cortex to the striatal matrix, which is known to project into pallidonigral circuits including the striatonigrocollicular pathway of the saccadic eye movement system. Furthermore, functionally distinct premotor areas near the oculomotor fields often systematically projected to striatal zones adjacent to oculomotor field projections, suggesting an anatomical basis for potential interaction of these inputs within the striatum. We propose that parallel processing is not the exclusive principle of organization of forebrain circuits associated with the basal ganglia. Rather, patterns of both convergence and divergence are present and are likely to depend on multiple functional and developmental constraints.
1. In this study, the movement-related activity of putamen neurons was investigated in behaving monkeys. The objective of the study was to examine whether the activity occurring in phase with body movements is directly related to the movement per se by encoding movement parameters or whether it is dependent on the circumstances in which the movement is performed. 2. Sensorially triggered arm movements were used as a behavioral task. A sequence of three visually triggered repetitive flexion-extensions of the elbow joint across the target were followed by the delivery of a juice reward. 3. There are two classes of putamen cells: type I, with tonic spontaneous discharges (2-7 Hz) and broad extracellularly recorded action potentials, and type II, with very low spontaneous discharge rate (less than 1 Hz). The movement-related phasic discharges occur exclusively in type II cells. 4. The movement-related activity of type II cells is classified into two contrasting types of cells: type IIa that exhibit burst discharges preceding the first movement of a sequence of repetitive arm or orofacial movements but that are almost inactive during succeeding movements, and type IIb that show movement-locked burst discharges with one-to-one correspondence. The somatotopic location of the cells was identified by microstimulation and/or sensory responses to passive somatosensory manipulation of the periphery. 5. The activities of type IIa cells occur with a short and fairly constant latency after the visual trigger stimulus and cease as soon as the sequence of the learned movements is initiated. In the condition in which the monkey attended to the visual trigger stimulus without initiating learned movements and waited for the delivery of juice reward at a fixed time after the stimulus, type IIa cells exhibited slight but consistent phasic discharges after the visual stimulus with short latency. This indicates that the type IIa cells have a visuomovement property. The type IIb cells, on the other hand, have a longer latency of activity after the visual trigger than type IIa cells and do not have the visuomovement property. 6. The type IIa cells change their activity pattern depending on whether the direction of initial movement is predictable before the trigger stimulus or not. 7. The activities of type IIa cells in the arm area of the putamen precede the electromyogram (EMG) of prime mover muscles by greater than 100 ms on average, whereas most type IIb cells are activated after the EMG during a learned arm-movement task.(ABSTRACT TRUNCATED AT 400 WORDS)
1. Tonically active neurons (TANs) in the primate striatum develop transient responses to sensory conditioning stimuli during behavioral training in classical conditioning tasks. In this study we examined the temporal characteristics of such TAN responses and mapped the sites of TANs responding to auditory and visual conditioned stimuli in the striatum in macaque monkeys. We further mapped the locations of TANs recorded acutely in the squirrel monkey striatum in relation to the neurochemically distinguished striosome and matrix compartments of the striatum, and made quantitative comparisons between the densities and compartmental distributions of TANs and those of four major types of striatal interneuron identified by histochemical and immunohistochemical staining. 2. We made recordings from 858 TANs at different sites in the striatum in two behaving macaque monkeys at different times during training with auditory (click) and visual (light-emitting diode flash) conditioning stimuli. TANs distributed across large parts of the striatum developed responses to the conditioning stimuli. The responses comprised a decrement of tonic firing (pause) followed by a rebound excitation. Measurements were made of the onsets, offsets, and durations of the pauses of individual TANs and of the interspike intervals (ISIs) of the same cells. 3. The mean duration of the pause responses (268.3 ms) was greater than the mean ISI of the same neurons (181 ms), suggesting that the pause represents an active suppression of TAN firing. The coefficient of variation (CV) for the pause responses was 0.28, compared with a CV of 0.63 for the same cells' ISIs. The population CV for the pauses was 0.16, compared with a population CV of 0.20 for the ISIs. These data, together with temporal analysis of the responses and population histograms, suggest that the pauses became temporally aligned across large parts of the striatum after learning. Analyses of variance (ANOVAs) were carried out to determine whether there were differences in the onset and offset latencies of the pause response or in the durations of the pause responses for TANs at different sites. These analyses suggested that, with rare exceptions, there was no difference in the timing of the TAN responses across large (> 10 mm3) parts of the striatum. 4. Comparisons of TAN responses in different regions of the striatum showed that, for responses to a given modality of conditioned stimulus, there were no significant differences in pause offset times for TANs recorded in the caudate nucleus or putamen, or for TANs recorded in more anterior or more posterior parts of these nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)
Dysfunction of the nigrostriatal dopamine system results in marked disorders of movement such as occur in Parkinson's disease.
Functions of this dopamine-containing projection system were examined in monkeys trained in a classical conditioning task,
and the effects of striatal dopamine depletion were tested. Unilateral dopamine loss substantially reduced the acquired sensory
responsiveness of striatal neurons monitored electrophysiologically. This effect was ipsilateral and selective, and could
be reversed by apomorphine. These results suggest that the primate nigrostriatal system modulates expression of neuronal response
plasticity in the striatum during sensorimotor learning.
The basal ganglia are neural structures within the motor and cognitive control circuits in the mammalian forebrain and are
interconnected with the neocortex by multiple loops. Dysfunction in these parallel loops caused by damage to the striatum
results in major defects in voluntary movement, exemplified in Parkinson's disease and Huntington's disease. These parallel
loops have a distributed modular architecture resembling local expert architectures of computational learning models. During
sensorimotor learning, such distributed networks may be coordinated by widely spaced striatal interneurons that acquire response
properties on the basis of experienced reward.
The basal ganglia have been implicated in motor planning and motor learning. In the study reported here, we directly tested for response plasticity in striatal neurons of macaque monkeys undergoing Pavlovian conditioning. To focus the study, we recorded from the tonically active neurons (TANs) of the striatum, which are known to respond to conditioned sensory stimuli that signal reward delivery and elicit behavioral reactions. The activities of 858 TANs were recorded extracellularly from the striatum in alert behaving macaque monkeys before, during, and after the acquisition of a classical conditioning task. Two monkeys were trained to lick reward juice delivered on a spoon simultaneously with the presentation of a click. Almost no licks were triggered by the cues at the start of training, but by the fifth day more than 90% of licks were triggered, and values were near 100% for the remainder of the 3 week training period. In the striatum, only a small number of TANs responded to the clicks at the start before conditioning (about 17%). During training, the numbers of responding TANs gradually increased, so that by the end of training more than 50-70% of the TANs recorded (51.3-73.5%) became responsive to the clicks. The responses consisted of a pause in firing that occurred approximately 90 msec after the click and that was in some cells preceded by a brief activation and in most cells was followed by a rebound excitation. Prolonged recordings from single TANs (n = 6) showed that individual TANs can acquire a conditioned response within at least as short a time as 10 min. TANs retained such responsiveness after overtraining, and also after a 4 week intermission in training. When the monkey was trained to receive rewards in relation to a new conditioning stimulus, TANs were capable of switching their sensory response to the new stimulus. Histological reconstruction showed that the TANs that became responsive were broadly distributed in the region of striatum explored, which included the dorsal half to two-thirds of the caudate nucleus and putamen over a large anteroposterior span. We conclude that, during the acquisition of a sensorimotor association, TANs widely distributed through the striatum become responsive to sensory stimuli that induce conditioned behavior. This distributed change in activity could serve to modulate the activity of surrounding projection neurons in the striatum engaged in mediating learned behavior.
1. Previous studies indicate that tonically active neurons (TANs) are the cholinergic interneurons of the striatum and predict that their activity is synchronized. To test whether TANs do fire synchronously, and whether dopamine depletion affects their synchronization, we recorded the simultaneous activity of several TANs in the putamens of two vervet monkeys before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. 2. Cross-correlation analysis revealed that most pairs of TANS (33 of 54; 61.1%) fire synchronously at +/- 60-ms delay. Correlated activity was more common between neurons with characteristic response to reward (17 of 19 pairs; 89.5%). 3. Cross-correlation study of 24 triplets of TANS showed synchronization of spiking activity of all 3 TANS in only 29.2% of cases (7 of 24 triplets). Correlated activity of two of three possible pairs was found in 25% of the cases. 4. After MPTP treatment and the development of parkinsonian symptoms, most TANS' auto- and cross-correlograms (22 of 28 units; 78.6%; and 23 of 28 pairs; 82.1%) became oscillatory. The number of correlated pairs was slightly increased (24 of 28; 85.7%). The strength of the synchronization was not significantly different from the normal values. 5. These findings support the notion that TANs function as distributed, partially overlapping synchronized networks. However, a normal dopaminergic system is not essential for synchronization of TANs; on the contrary, dopaminergic activity may even have a desynchronizing effect on the basal ganglia's system.
The basal ganglia are a highly interconnected network of nuclei essential for the modulation and execution of voluntary behavior. The neostriatum is the principal input and one of the principal controllers of the output of the basal ganglia. Neostriatal projection neurons seem to be dynamically and powerfully controlled by GABAergic inputs, but the source(s) and physiological properties of these inputs remain unclear. Here we use paired whole-cell recordings to show that this inhibition derives from small populations of GABAergic interneurons that are themselves interconnected through functional electrotonic synapses. Inhibitory synaptic potentials generated from single interneurons are sufficiently powerful to delay or entirely block the generation of action potentials in a large number of projection neurons simultaneously.
Memories for habits and skills (“implicit or procedural memory”) and memories for facts (“explicit or episodic memory”) are
built up in different brain systems and are vulnerable to different neurodegenerative disorders in humans. So that the striatum-based
mechanisms underlying habit formation could be studied, chronic recordings from ensembles of striatal neurons were made with
multiple tetrodes as rats learned a T-maze procedural task. Large and widely distributed changes in the neuronal activity
patterns occurred in the sensorimotor striatum during behavioral acquisition, culminating in task-related activity emphasizing
the beginning and end of the automatized procedure. The new ensemble patterns remained stable during weeks of subsequent performance
of the same task. These results suggest that the encoding of action in the sensorimotor striatum undergoes dynamic reorganization
as habit learning proceeds.
The striosome and matrix compartments of the striatum are clearly identified by their neurochemical expression patterns and anatomical connections. To determine whether these compartments are distinguishable functionally, we used [14C]deoxyglucose metabolic mapping in the rat and tested whether neutral behavioral states (free movement, gentle restraint, and focal tactile stimulation under gentle restraint) were associated with regions of high metabolic activity in the matrix, in striosomes, or in both. We identified metabolic peaks in the striatum by means of image analysis, striosome-matrix boundaries by [3H]naloxone binding, and primary somatosensory corticostriatal input clusters by injections of anterograde tracer into electrophysiologically identified sites in SI. Peak metabolic activity was primarily confined to the matrix compartment under each behavioral condition. These findings show that during relatively neutral behavioral conditions the balance of activity between the two compartments favors the matrix and suggest that this balance is present in the striatum as part of normal behavior and processing of afferent activity.
GABAergic interneurons appear to play a fundamental role in the functioning of the neostriatum by modulating the spiking of striatal projection neurons with great efficacy. The powerful and strongly divergent output of the GABAergic interneurons neurons suggests that modulation of their activity may be particularly effective at controlling the functioning of the entire neostriatal circuitry. Acetylcholine is one of the main modulators of striatal functioning. The effects of acetylcholine on fast-spiking (FS) GABAergic interneurons were studied with whole-cell recording in an in vitro slice preparation. Acetylcholine exerted two distinct effects on fast-spiking interneurons. Acetylcholine directly depolarized FS interneurons by acting on nondesensitizing soma-dendritic nicotinic receptors. In addition, acetylcholine attenuated the GABAergic inhibition of projection neurons by fast-spiking interneurons through activation of presynaptic muscarinic receptors. It is suggested that the nicotinic excitation of FS interneurons may play an important role in translating the effect of the brief behaviorally contingent cessation of firing of the tonically active cholinergic interneurons to the output neurons of the neostriatum. In contrast, the muscarinic presynaptic inhibitory mechanism may be engaged primarily during longer-lasting elevations of extracellular acetylcholine levels.
Although the mammalian basal ganglia have long been implicated in motor behavior, it is generally recognized that the behavioral functions of this subcortical group of structures are not exclusively motoric in nature. Extensive evidence now indicates a role for the basal ganglia, in particular the dorsal striatum, in learning and memory. One prominent hypothesis is that this brain region mediates a form of learning in which stimulus-response (S-R) associations or habits are incrementally acquired. Support for this hypothesis is provided by numerous neurobehavioral studies in different mammalian species, including rats, monkeys, and humans. In rats and monkeys, localized brain lesion and pharmacological approaches have been used to examine the role of the basal ganglia in S-R learning. In humans, study of patients with neurodegenerative diseases that compromise the basal ganglia, as well as research using brain neuroimaging techniques, also provide evidence of a role for the basal ganglia in habit learning. Several of these studies have dissociated the role of the basal ganglia in S-R learning from those of a cognitive or declarative medial temporal lobe memory system that includes the hippocampus as a primary component. Evidence suggests that during learning, basal ganglia and medial temporal lobe memory systems are activated simultaneously and that in some learning situations competitive interference exists between these two systems.
Interneurons are critical for shaping neuronal circuit activity in many parts of the central nervous system. To study interneuron function in the basal ganglia, we tested and characterized an NK-1 receptor-based method for targeted ablation of specific classes of interneuron in the striatum. Our findings demonstrate that the neurotoxin SP-PE35, a substance P-Pseudomonas exotoxin conjugate, selectively targets striatal cholinergic and nitric oxide synthase/somatostatinergic interneurons when injected locally into the striatum. The effects of this selective cell targeting encompassed alterations in both behavioral and neural responses to dopaminergic stimulation, including altered patterns of early-gene response in striosomes and matrix. We conclude that NK-1-bearing local circuit neurons of the striatum regulate the differential responses of striatal projection neurons to dopamine-mediated signaling.
Complex biological systems such as human language and the genetic code are characterized by explicit markers at the beginning
and end of functional sequences. We report here that macaque prefrontal cortical neurons exhibit phasic peaks of spike activity
that occur at the beginning and endpoint of sequential oculomotor saccade performance and have the properties of dynamic start-
and end-state encoders accompanying responses to sequential actions. Sequence bounding may thus reflect a general mechanism
for encoding biological information.
Synchronous oscillatory activity has been observed in a range of neural networks from invertebrate nervous systems to the human frontal cortex. In humans and other primates, sensorimotor regions of the neocortex exhibit synchronous oscillations in the beta-frequency band (approximately 15-30 Hz), and these are also prominent in the cerebellum, a brainstem sensorimotor region. However, recordings in the basal ganglia have suggested that such beta-band oscillations are not normally a primary feature of these structures. Instead, they become a dominant feature of neural activity in the basal ganglia in Parkinson's disease and in parkinsonian states induced by dopamine depletion in experimental animals. Here we demonstrate that when multiple electrodes are used to record local field potentials, 10-25 Hz oscillations can be readily detected in the striatum of normal macaque monkeys. These normally occurring oscillations are highly synchronous across large regions of the striatum. Furthermore, they are subject to dynamic modulation when monkeys perform a simple motor task to earn rewards. In the striatal region representing oculomotor activity, we found that small focal zones could pop in and out of synchrony as the monkeys made saccadic eye movements, suggesting that the broadly synchronous oscillatory activity interfaces with modular spatiotemporal patterns of task-related activity. We suggest that the background beta-band oscillations in the striatum could help to focus action-selection network functions of cortico-basal ganglia circuits.
Understanding how an animal's ability to learn relates to neural activity or is altered by lesions, different attentional states, pharmacological interventions, or genetic manipulations are central questions in neuroscience. Although learning is a dynamic process, current analyses do not use dynamic estimation methods, require many trials across many animals to establish the occurrence of learning, and provide no consensus as how best to identify when learning has occurred. We develop a state-space model paradigm to characterize learning as the probability of a correct response as a function of trial number (learning curve). We compute the learning curve and its confidence intervals using a state-space smoothing algorithm and define the learning trial as the first trial on which there is reasonable certainty (>0.95) that a subject performs better than chance for the balance of the experiment. For a range of simulated learning experiments, the smoothing algorithm estimated learning curves with smaller mean integrated squared error and identified the learning trials with greater reliability than commonly used methods. The smoothing algorithm tracked easily the rapid learning of a monkey during a single session of an association learning experiment and identified learning 2 to 4 d earlier than accepted criteria for a rat in a 47 d procedural learning experiment. Our state-space paradigm estimates learning curves for single animals, gives a precise definition of learning, and suggests a coherent statistical framework for the design and analysis of learning experiments that could reduce the number of animals and trials per animal that these studies require.
The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of learning by selectively ablating the striatal cholinergic neurons with use of immunotoxin-mediated cell targeting. We show that selective ablation of cholinergic neurons in the striatum impairs procedural learning in the tone-cued T-maze memory task. Spatial delayed alternation in the T-maze learning test is also impaired by cholinergic cell elimination. In contrast, the deficit in striatal ACh transmission has no effect on motor learning in the rota-rod test or spatial learning in the Morris water-maze test or on contextual- and tone-cued conditioning fear responses. We also report that cholinergic cell elimination adaptively up-regulates nicotinic ACh receptors not only within the striatum but also in the cerebral cortex and substantia nigra. The present investigation indicates that cholinergic modulation in the local striatal circuit plays a pivotal role in regulation of neural circuitry involving reward-related procedural learning and working memory.
1. There are indications that the execution of behavioral sequences involves the basal ganglia. In this study we examined the role of the caudate nucleus in the construction, storage, and execution of spatial plans. 2. Two monkeys (Macaca mulatta) were trained to perform sequences of saccades and arm movements. The animals had to remember the order of illumination, variable from one sequence to another, of three fixed spatial targets. After a delay, they had to visually orient toward, and press each target in the same order. Six different sequences were executed on the basis of the order of illumination of the targets. Single cell activity was recorded from the four caudate nuclei of the two monkeys. 3. Neural activity was analyzed in each sequence during 10 different periods: the instruction period in which the targets were illuminated, the three orientation periods toward the different targets, the three postsaccadic periods, and the three periods of target pressing. Statistical comparisons were made to detect differences between the different sequences with respect to activity in each period (sequence specificity). 4. A total of 2,100 neurons were studied, of which 387 were task related. The task-related cells were found in both the head and the body of the caudate nucleus. 5. During central fixation, anticipatory activity (n = 81) preceded onset of specific events. Four groups were considered: 1) neurons (n = 46) anticipating offset of the central fixation point, 2) neurons (n = 7) anticipating the illumination of any target, regardless of its spatial position or order of presentation (rank), 3) neurons (n = 17) anticipating the illumination of the first target, regardless of its spatial position, and 4) neurons (n = 11) anticipating the illumination of a given target, regardless of its rank. 6. Phasic visual responses to target onset were observed in 48 cells. The cells responded primarily to the contralateral and upper targets. In a majority (n = 35), visual responses were modulated by the rank of the target(s). Many cells (n = 20) responded only if the corresponding target was first; other cells responded only if the target was second or if it had complex time relationships with the other targets. 7. The responses of the cells to the same instruction stimuli repeated twice in a row, and under the condition that the animal did not behaviorally use the first instruction in between, were tested. More than one-third of the tested cells (n = 14) did not respond, or responded very weakly, to the second instruction.(ABSTRACT TRUNCATED AT 400 WORDS)
Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.
The major goal of this study was to determine whether the activity of single cells in the primate putamen was better related to the direction of limb movement or to the underlying pattern of muscular activity. In addition, the neural responses to load application were studied in order to determine whether the same neurons were also responsive to somatosensory stimuli. Two rhesus monkeys were trained to perform a visuomotor arm tracking task which required elbow flexion/extension movements with assisting and opposing loads in order to dissociate the direction of elbow movement from the pattern of muscular activity required for the movement. Neurons in the putamen were selected for study only if they were related both to the task and to arm movements outside the task. Most (96%) of the cells studied responded to load application: 36% of these showed short-latency(< 50 ms), “sensory” responses. Forty-four percent of neurons had significant relations to the level of static load as the animal held the arm stationary against the steady loads: in general, static load effects were relatively weak. During the elbow flexion/extension movements in the task, 76% of cells had significant relations to the direction of movement, and 52% of neurons had significant dynamic relations to the level of load. Half of all neurons studied were primarily related to the direction of movement independent of the load. Only thirteen percent of cells in the putamen had a pattern of activity similar to that of muscles. These results indicate that neuronal activity in the putamen is predominantly related to the direction of limb movement rather than to the activity of particular muscles and that the basal ganglia may play a role in the specification of parameters of movement independent of the activity of specific muscles. These results also indicate that the basal ganglia receive proprioceptive input which may be used in the control of ongoing movement.
Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.
1. The basal ganglia of primates receive somatosensory input carried largely by corticostriatal fibers. To determine whether map-transformations occur in this corticostriatal system, we investigated how electrophysiologically defined regions of the primary somatosensory cortex (SI) project to the striatum in the squirrel monkey (Saimiri sciureus). Receptive fields in the hand, mouth, and foot representations of cortical areas 3a, 3b, and 1 were mapped by multiunit recording; and small volumes of distinguishable anterograde tracers were injected into different body-part representations in single SI areas. 2. Analysis of labeled projections established that at least four types of systematic remapping occur in the primate corticostriatal system. 1) An area of cortex representing a single body part sends fibers that diverge to innervate multiple regions in the putamen, forming branching, patchy fields that are densest in the lateral putamen. The fields do not form elongated cylindrical forms; rather, they are nearly as extended mediolaterally as they are rostrocaudally. 2) Cortical regions representing hand, mouth, and foot send globally somatotopic, nonoverlapping projections to the putamen, but regions with closely related representations (such as those of the thumb and 5th finger in area 3b) send convergent, overlapping corticostriatal projections. The overlap is fairly precise in the caudal putamen, but in the rostral putamen the densest zones of the projections do not overlap. 3) Regions representing homologous body parts in different SI cortical areas send projections that converge in the putamen. This was true of paired projections from areas 3a and 3b, and from areas 3b and 1. Thus corticostriatal inputs representing distinct somatosensory submodalities can project to the same local regions within the striatum. Convergence is not always complete, however: in the rostral putamen of two cases comparing projections from areas 3a and 1, the densest zones of the projections did not overlap. 4) All projections from SI avoid striosomes and innervate discrete zones within the matrix. 3. These experiments demonstrate that the somatosensory representations of the body are reorganized as they are projected from SI to the somatosensory sector of the primate putamen. This remapping suggests that the striatal representation of the body may be functionally distinct from that of each area of SI. The patchy projections may provide a basis for redistribution of somatosensory information to discrete output systems in the basal ganglia. Transformations in the corticostriatal system could thus be designed for modulating different movement-related programs.
The basal ganglia, with their inhibitory efferents, control motor outputs either directly by their projections to the midbrain motor regions or indirectly through the thalamic nuclei. Neural mechanisms in the basal ganglia act selectively to remove or enhance the inhibition so that different combinations of motor signals, which may act as neural templates for motor learning, are formed.
Single cell recordings in awake monkeys and cats have demonstrated that individual body parts are represented within striatal subregions receiving projections from somatic sensorimotor cortex. Literature indicating that the lateral striatum of the rat receives similar cortical inputs and subserves sensorimotor functions prompted a study of whether this subregion contains similar representations of the body. Single cell recordings were obtained from 923 neurons of 24 awake, unrestrained rats. Of 788 neurons categorized according to body part, 264 (34%) discharged in relation to active movement, passive manipulation, and/or cutaneous stimulation of a particular part of the body; the remainder were related to global, whole body movement (38%) or were unresponsive (28%). Neurons related to individual body parts were recorded throughout the entire anterior-posterior extent of the dorsolateral striatum (+ 1.60 to –2.12 mm A-P, from bregma), intermingled among each other in all 3 dimensions. Two topographic arrangements were observed. First, neurons that fired rhythmically, in phase with low frequency (5–6 Hz) whisking of the vibrissae were segregated in the caudal striatum (–0.2 to –2.12 mm A-P) from neurons related to other body parts, which were distributed from + 1.6 to –0.8 mm A-P. Second, representations of the head and face were located ventral to those of the limbs, despite substantial overlap in their overall distributions. A prominent feature of individual electrode tracks was the clustering together of cells related to the same body part.
The sources of afferent input to the striatum (caudate nucleus and putamen) suggest that this structure may be engaged in neuronal processes related to the initiation of movement. We found that 26% of 508 neurons in both parts of the striatum were activated during the presentation of visual signals which prepared the animals for the execution or withholding of individual arm reaching movements. In a second task, 20% of 382 striatal neurons were activated up to 3 s before self-initiated, non automatic and purposive arm movements which were performed in the complete absence of phasic external stimuli. The data demonstrate an involvement of the striatum in externally and internally generated processes which are related to presetting mechanisms during the initiation of behavioral acts.
The striatum is known to have a compartmental organization in which histochemically defined zones called striosomes form branched 3-dimensional labyrinths embedded within the surrounding matrix. We explored how fiber projections from cortical somatic sensory areas representing cutaneous and deep-receptor inputs are organized in relation to this striatal architecture. Areas SI and 3a were mapped electrophysiologically, and distinguishable anterograde tracers (wheat germ agglutinin-HRP and 35S-methionine) were injected into physiologically identified loci. Primary somatic sensory corticostriatal projections were confined to a small, well-defined sector in the dorsolateral corner of the ipsilateral striatum. The somatic sensory afferents were arranged according to a coherent global body map in which rostral body parts were represented more laterally than caudal body parts. Single cortical loci innervated branched and clustered striatal zones that were reminiscent of the striosomes in their range of sizes and shapes yet lay strictly within the extrastriosomal matrix. In contrast to the global orderliness of the striatal body map, there were clear examples of locally complex patterns in which functionally distinct inputs interdigitated with each other. These patterns were often, but not always, produced when corticostriatal afferents carrying different submodality types were labeled. These findings demonstrate the existence of striosome-like striatal compartments within the seemingly uniform extrastriosomal matrix. The principle of mosaic organization thus holds throughout the tissue of the somatic sensory striatum. The striatal architecture delineated here could provide the anatomical substrate for computations requiring cross-modality comparisons within the framework of an overall somatotopy. If a similar multicompartmental architecture also characterizes other striatal regions, as seems likely, it may set general constraints on the nature of associative processing within the striatum as a whole.
The autoradiographic technique was used to examine the projection from the digit and wrist area of the precentral gyrus to the putamen in two macaque monkeys. Motor responses elicited by intracortical microstimulation were mapped to guide selection of the site of injection of isotope. Additionally, an electrophysiological study of the activity of putamen neurons during voluntary movements of the distal arm in an awake monkey was performed prior to the anatomical study in one of the animals. Two major findings resulted from this study. Firstly, the area of representation of the digits and wrist in area 4 gives rise to a substantial projection to the putamen. The distribution of terminals consisted of a simple pattern of clusters at anterior levels of the putamen. At caudal levels in the putamen, the clusters merged into a single diagonal band of label. This basic pattern was found to be virtually identical in the two monkeys. Secondly, the location of neurons in the putamen which were activated during voluntary movements of the distal arm was closely associated with the terminal distribution of fibers from the digit and wrist zone of area 4. These data provide strong evidence to support the idea that the putamen is concerned with motor function of distal muscles of the arm, and that the topographic characteristics of the corticoputamen projection are closely related to the physiological properties of individual neurons in the putamen.
In order to clarify the functional organization of the putamen and the nature of sensory inputs to this structure we studied the relation of single cell activity to active movements and somatosensory stimulation in the awake primate. Neurons (N = 707) were categorized on the basis of their relation to active movements or responses to sensory stimulation of individual body parts. 38% of neurons studied were related to the arm, 9% to the leg, 11% to the mouth or face, and 3% to axial portions of the body. The remaining neurons exhibited non-specific activation which could not be confidently localized to an individual body part (12%) or did not respond during the examination (26%). The high proportion of arm neurons was due to the focus of this study on cells related to arm movements. A large proportion (41%; N = 270) of the "arm" neurons was responsive to somatosensory stimulation. For these neurons the most effective stimulus (82%) was passive joint rotation. Six (5%) of the arm neurons responded to cutaneous stimulation. The putamen was found to be somatotopically organized. Neurons related to different body parts (leg, arm, and face) were segregated, and each body part was represented over a long anteroposterior extent of the nucleus. Clusters of 2-5 neurons with similar relations to active movements or responsive to passive movements of a single joint were often encountered over a 100-500 mu distance. Clusters of neurons with sensory driving were organized by joints. Rather than a single elbow or shoulder area, multiple clusters of neurons related to each joint were widely distributed over a long anteroposterior extent of the nucleus and were adjacent to clusters of neurons related to other joints of the arm. These clusters of neurons with similar functional properties may correspond to the subunits of the striatum which have been revealed by anatomic and morphologic studies. We propose that these clusters of neurons with similar functional properties represent the basic functional units of the striatum in a manner analogous to the functional columns of the neocortex.
1. There are indications that the execution of behavioral sequences involves the basal ganglia. In this study we examined the role of the caudate nucleus in the construction, storage, and execution of spatial plans. 2. Two monkeys (Macaca mulatta) were trained to perform sequences of saccades and arm movements. The animals had to remember the order of illumination, variable from one sequence to another, of three fixed spatial targets. After a delay, they had to visually orient toward, and press each target in the same order. Six different sequences were executed on the basis of the order of illumination of the targets. Single cell activity was recorded from the four caudate nuclei of the two monkeys. 3. Neural activity was analyzed in each sequence during 10 different periods: the instruction period in which the targets were illuminated, the three orientation periods toward the different targets, the three postsaccadic periods, and the three periods of target pressing. Statistical comparisons were made to detect differences between the different sequences with respect to activity in each period (sequence specificity). 4. A total of 2,100 neurons were studied, of which 387 were task related. The task-related cells were found in both the head and the body of the caudate nucleus. 5. During central fixation, anticipatory activity (n = 81) preceded onset of specific events. Four groups were considered: 1) neurons (n = 46) anticipating offset of the central fixation point, 2) neurons (n = 7) anticipating the illumination of any target, regardless of its spatial position or order of presentation (rank), 3) neurons (n = 17) anticipating the illumination of the first target, regardless of its spatial position, and 4) neurons (n = 11) anticipating the illumination of a given target, regardless of its rank. 6. Phasic visual responses to target onset were observed in 48 cells. The cells responded primarily to the contralateral and upper targets. In a majority (n = 35), visual responses were modulated by the rank of the target(s). Many cells (n = 20) responded only if the corresponding target was first; other cells responded only if the target was second or if it had complex time relationships with the other targets. 7. The responses of the cells to the same instruction stimuli repeated twice in a row, and under the condition that the animal did not behaviorally use the first instruction in between, were tested. More than one-third of the tested cells (n = 14) did not respond, or responded very weakly, to the second instruction.(ABSTRACT TRUNCATED AT 400 WORDS)
The basal ganglia receive massive inputs from the neocortex and send outputs that exert both inhibitory and disinhibitory control over parts of the frontal cortex and brainstem. Between these basal ganglia inputs and outputs lies the striatum, which receives most of the cortical afferents and projects to the basal ganglia output nuclei--the globus pallidus and substantia nigra. To analyze this system we conjointly labeled, in squirrel monkeys, sensorimotor cortical inputs to the striatum and striatal outputs to the globus pallidus. Anterograde tracers were injected into the motor (MI) and somatosensory (SI) cortical body maps, at sites determined by electrophysiological stimulation and recording. Retrograde tracers were stereotaxically injected into the external and internal pallidal segments (GPe and GPi). We found that multiple dispersed modules ("matrisomes") in the putamen that all received inputs from single body-part representations in sensorimotor cortex could, in turn, send convergent outputs to single sites in the pallidum. This divergence-reconvergence pattern was found for both GPe and GPi sites, and for inputs from both SI and MI cortex. Thus, information from a single functional region in the cortex can be split up at the striatal stage only to be brought back together in the pallidum. The temporary divergence may increase lateral interactions between sensorimotor matrisomes, as well as between matrisomes and striosomes. One function of striatal modularity may thus be to set up an associative network in the striatum, which might contribute to sensorimotor learning. We also found that some sets of matrisomes did not receive strong sensorimotor inputs, even though they projected to regions of GPe and GPi that are near the sensorimotor-recipient zones described above. Thus, the matrisomal system may sort MI/SI inputs and other inputs before transfer to paired regions of GPe and GPi.
The striatum receives inputs from different areas of the cerebral cortex, including association cortical areas far on in the hierarchy of cortical information processing as well as the sensori-motor cortex, and has connections via the globus pallidus and substantia nigra to the thalamus and thence to premotor and prefrontal cortical areas. Recordings of the activity of neurons in different parts of the striatum of primates show that they have the following properties: 1) neurons in much of the putamen, which receives inputs from the sensori-motor cortex, have activity related to movements; 2) neurons in the caudate nucleus, which receives from the association cortex, have activity related for example to environmental stimuli which signal preparation for or initiation of behavioral responses; 3) neurons in the tail of the caudate nucleus, which receives strongly from the inferior temporal visual cortex, respond when a patterned visual stimulus changes; 4) some neurons in the posterior ventral putamen, which receives from the inferior temporal visual cortex and the prefrontal cortex, respond in a visual short term memory task, delayed match to sample. The neurons responded in the delay period, or differentially to match and non-match stimuli. These neurons did not respond in an auditory delayed match to sample task, so that their activity was not related to movement per se, but was instead more closely related to visual inputs relevant to a memory task; 5) some neurons in the ventral striatum (including the nucleus accumbens), which receives from limbic structures such as the amygdala and hippocampus, respond to stimuli associated with reinforcement or to novel stimuli. It is concluded that there is considerable segregation of function within the striatum. It is suggested that there is an opportunity for inputs which originate from different parts of the cerebral cortex to interact, via a first stage of convergence in the striatum, and by a further stage of convergence on the dendrites of single neurons in the globus pallidus and substantia nigra; and that both these parts of the basal ganglia may learn associations between the different signals they receive. The result of this convergence and learning is that the basal ganglia provide a way for cortical areas far on in the hierarchy of information processing to become linked during motor learning to particular sequences of movements, and thus to be involved in the execution of motor programs.
Single cell activity was recorded from the monkey caudate nucleus. The animal had to execute motor and oculomotor sequences based on memorized information. In each trial, the monkey had to remember the order of illumination of three fixed spatial targets. After a delay, the animal had to press the targets in the same sequence. The "task-related" cells were activated by onset of the targets and on execution of saccades or arm movements. In a majority of cells, activation did not depend only on the retinal position of the stimuli or on the spatial parameters of gaze and arm movements, but was contingent on the particular sequence in which the targets were illuminated or the movements were performed.
The neostriatum is the largest component of the basal ganglia, and the main recipient of afferents to the basal ganglia from the cerebral cortex and thalamus. Studies of the cellular organization of the neostriatum have focused upon the spiny projection neurones, which represent the vast majority of neurones, but the identity and functions of interneurones in this structure have remained enigmatic despite decades of study. Recently, the discovery of cytochemical markers that are specific for each of the major classes of striatal interneurones, and the combination of this with intracellular recording and staining, has revealed the identities of interneurones and some of their functional characteristics in a way that could not have been imagined by the classical morphologists. These methods also suggest some possible modes of action of interneurones in the neostriatal circuitry.
Striatal neurons can be classified as movement- and nonmovement-related depending on their ability to change firing rate in close temporal association with spontaneous movement in an open-field arena. The present study assessed the location of these cell types within the compartmental organization of the striatum by combining single-unit recording techniques in freely moving rats with calbindin immunohistochemistry. Movement-related neurons were found predominately either in the matrix or along the matrix-striosome border. Most of these neurons were nonselective in that they increased activity whenever the animals changed from a quiet resting posture to any form of behavioral activation (e.g., grooming, locomotion, rearing). The remaining neurons in this group responded exclusively to movements of the head. Nonselective units discharged at a significantly slower rate than head-movement units during both quiet rest and periods of actual movement. Nonmovement-related neurons, which failed to show a reliable change in activity to overt behavior, comprised a relatively small portion of the neuronal sample but were also located in either the matrix or along the matrix-striosome border. Collectively, these results suggest that even though striatal neurons can be distinguished on the basis of their responsiveness to ongoing behavior in an open-field paradigm, such distinctions are not clearly linked to sites within the matrix or its striosomal borders.
The basal ganglia comprise several nuclei in the forebrain, diencephalon, and midbrain thought to play a significant role in the control of posture and movement. It is well recognized that people with degenerative diseases of the basal ganglia suffer from rigidly held abnormal body postures, slowing of movement, involuntary movements, or a combination of these a abnormalities. However, it has not been agreed just what the basal ganglia contribute to normal movement. Recent advances in knowledge of the basal ganglia circuitry, activity of basal ganglia neurons during movement, and the effect of basal ganglia lesions have led to a new hypothesis of basal ganglia function. The hypothesis states that the basal ganglia do not generate movements. Instead, when voluntary movement is generated by cerebral cortical and cerebellar mechanisms, the basal ganglia act broadly to inhibit competing motor mechanisms that would otherwise interfere with the desired movement. Simultaneously, inhibition is removed focally from the desired motor mechanisms to allow that movement to proceed. Inability to inhibit competing motor programs results in slow movements, abnormal postures and involuntary muscle activity.
Current understanding of basal ganglia function emphasizes their involvement in the focal, context-dependent release of motor and cognitive circuits in the brainstem and frontal lobes. How such selective action can arise despite the existence of massively convergent inputs from the cerebral cortex is unknown. However, anatomical work has suggested that specificity could be achieved in corticostriatal circuits by modular patterns of convergent and divergent cortical inputs to striatal projection neurons. To test for such modular activation of striatal neurons, we electrically microstimulated physiologically identified sites in the primary somatosensory (SI) and primary motor (MI) cortex of the squirrel monkey. We compared the efferent fiber distributions anterogradely traced from these sites to the distributions of striatal neurons activated by microstimulation to express Fos- and Jun B-like immediate-early gene proteins. We show that the microstimulation of sensorimotor cortex induces Fos and Jun B expression in localized cell clusters in the putamen and that these clusters match the anatomical input fiber clusters (matrisomes). The modular activation of striatal neurons by sensorimotor cortex seems likely. Unexpectedly, >75% of the Fos-positive nuclei in densely labeled cell clusters were in enkephalin-immunoreactive neurons. This expression pattern suggests that the primate sensorimotor cortex exerts a differential influence on the enkephalinergic (indirect pathway) as opposed to the substance P/dynorphin (direct pathway) projection neurons of the putamen. The densely labeled clusters of Fos-labeled enkephalinergic neurons occurred within larger zones containing sparsely distributed Fos-labeled parvalbumin neurons. Moreover, when the cortical stimulation induced expression of Fos-like protein only in sparsely distributed neurons, almost every putamenal neuron expressing Fos was a parvalbumin-containing (GABAergic) interneuron. These patterns suggest a model in which the primate sensorimotor cortex can target parvalbumin-containing inhibitory interneurons, which in turn depress the remaining neuronal activity within and around matrisomes in a feed-forward manner until sufficient coherent cortical input can overcome the inhibition to influence selectively enkephalinergic projection neurons in the activated matrisomes. Tuning of cortical input by striatal interneurons thus may be an important mechanism by which broader anatomical connections are dynamically adjusted to achieve selective flow of information through the basal ganglia.
The basal ganglia have been shown to contribute to habit and stimulus-response (S-R) learning. These forms of learning have the property of slow acquisition and, in humans, can occur without conscious awareness. This paper proposes that one aspect of basal ganglia-based learning is the recoding of cortically derived information within the striatum. Modular corticostriatal projection patterns, demonstrated experimentally, are viewed as producing recoded templates suitable for the gradual selection of new input-output relations in cortico-basal ganglia loops. Recordings from striatal projection neurons and interneurons show that activity patterns in the striatum are modified gradually during the course of S-R learning. It is proposed that this recoding within the striatum can chunk the representations of motor and cognitive action sequences so that they can be implemented as performance units. This scheme generalizes Miller's notion of information chunking to action control. The formation and the efficient implementation of action chunks are viewed as being based on predictive signals. It is suggested that information chunking provides a mechanism for the acquisition and the expression of action repertoires that, without such information compression would be biologically unwieldy or difficult to implement. The learning and memory functions of the basal ganglia are thus seen as core features of the basal ganglia's influence on motor and cognitive pattern generators.
Recent studies have shown that multiple brain areas contribute to different stages and aspects of procedural learning. On the basis of a series of studies using a sequence-learning task with trial-and-error, we propose a hypothetical scheme in which a sequential procedure is acquired independently by two cortical systems, one using spatial coordinates and the other using motor coordinates. They are active preferentially in the early and late stages of learning, respectively. Both of the two systems are supported by loop circuits formed with the basal ganglia and the cerebellum, the former for reward-based evaluation and the latter