Comparison of learning-related neuronal activity in the dorsal premotor cortex and striatum

Previous studies have reported learning-related changes in neuronal activity during conditional visuomotor learning, also known as arbitrary sensorimotor mapping, conditional visual discrimination, and symbolic or endogenous mapping. Qualitatively similar observations have been reported for the dorsal premotor cortex, the supplementary eye field, the prefrontal cortex, the hippocampus, the striatum and the globus pallidus. The fact that cells in both the dorsal premotor cortex (PMd) and the basal ganglia show changes in activity during associative learning enables a test of the hypothesis that cortex and basal ganglia function in distributed architectures known as cortical-basal ganglionic modules or 'loops'. We reasoned that if these loops represent functional entities, as proposed, then learning-related changes in activity should occur simultaneously in both the cortical and striatal nodes of a loop. The present results confirmed this prediction; as monkeys learned conditional visuomotor associations, neurons in the premotor cortex and associated parts of the putamen changed their rates at approximately the same time. For the largest number of neurons, the evolution in neural activity occurred in close correspondence to the monkeys' learning curves. As a population, however, learning-related changes in activity continued after the monkeys reached an asymptote in performance.     

The role of ARX in cortical development

The ARX protein (encoded by the aristaless-related homeobox gene) is a member of the paired class of homeoproteins. More precisely, it is a member of the Aristaless subclass of proteins with a glutamine residue (Q) at the critical position 50 of the homeodomain (Q50). Through identification of diverse inherited or de novo mutations, genetic investigations of X-linked mental retardation conditions have demonstrated the implication of ARX in a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. These investigations have recently directed attention to the role of this gene in brain development. Analysis of its spatiotemporal localization profile have revealed expression mainly in telencephalic structures at all stages of development. Interestingly, in adult, ARX expression becomes restricted to a population of GABAergic neurons. Although the identification of the target genes regulated by ARX remains a crucial step to better understanding its role during brain development, studies of the role of ARX orthologs in different models have indicated that it is essential for important developmental processes such as proliferation, cell differentiation and neuronal migration.     

The role of serotonin in early cortical development

The cerebral cortex is widely innervated by serotonin (5-HT)-containing axons originating from neurons in the raphe nuclei. The early development of this monoamine system in the cortex prompted speculation long ago that it has important functions in cortical maturation and plasticity. Here we review evidence, derived from a plethora of studies and from our recent unpublished work, that supports an important role for 5-HT in a number of major events in the developing cortex, especially at the early stages. This evidence points to a regulatory role for 5-HT in neuronal proliferation, migration and differentiation, and in preventing apoptotic cell death.     

The associative striatum: organization of cortical projections to the dorsocentral striatum in rats

The dorsocentral striatum (DCS) is the major site of input from medial agranular cortex (AGm) and has been implicated as an associative striatal area that is part of a cortical-subcortical circuit involved in multimodal spatial functions involving directed attention. Anterograde axonal tracing was used to investigate the spatial organization of corticostriatal projections to DCS. Injections of biotinylated dextran amine were made into several cortical areas known to project to DCS based on retrograde tracing data. These included areas AGm, lateral agranular cortex (AGl), orbital cortex, posterior parietal cortex (PPC), and visual association cortex. We discovered a previously undescribed geometry whereby the projection from AGm is prominent within DCS and the main corticostriatal projections from areas other than AGm are situated around the periphery of DCS: visual association cortex dorsomedially, PPC dorsally, AGl laterally, and orbital cortex ventrally. Each of these cortical projections is also represented by less dense aggregates of terminal labeling within DCS, organized as focal patches and more diffuse labeling. Because these cortical areas are linked by corticocortical connections, the present findings indicate that interconnected cortical areas have convergent terminal fields in the region of DCS. These findings suggest that DCS is a central associative region of the dorsal striatum characterized by a high degree of corticostriatal convergence.     

The associative striatum: cortical and thalamic projections to the dorsocentral striatum in rats

Corticostriatal projections to the dorsocentral striatum (DCS) were investigated using retrograde fluorescent axonal tracing. The DCS is of interest because of its role in directed attention and recovery from multimodal hemispatial neglect following cortical lesions of medial agranular cortex (AGm), an association area that is its major source of cortical input. A key finding was that the multimodal posterior parietal cortex (PPC) also contributes substantial input to DCS. This is significant because PPC and AGm are linked by corticocortical connections and are both critical components of the circuitry involved in spatial processing and directed attention. Other cortical areas providing input to DCS include visual association areas, lateral agranular cortex and orbital cortex. These areas also have reciprocal connections with AGm and PPC. Less consistent labeling was seen in somatic sensorimotor areas FL, HL and Par 1. Thalamic afferents to DCS are prominent from the intralaminar, ventrolateral, mediodorsal, ventromedial, laterodorsal (LD) and lateral posterior (LP) nuclei. Collectively, these nuclei constitute the sources of thalamic input to cortical areas AGm and PPC. Nuclei LD and LP are only labeled with injections in dorsal DCS, the site of major input from PPC, and PPC receives its thalamic input from LD and LP. We conclude that DCS receives inputs from cortical and thalamic areas that are themselves linked by corticocortical and thalamocortical connections. These findings support the hypothesis that DCS is a key component of an associative network of cortical, striatal and thalamic regions involved in multimodal processing and directed attention.     

A comparison of abstract rules in the prefrontal cortex, premotor cortex, inferior temporal cortex, and striatum

The ability to use abstract rules or principles allows behavior to generalize from specific circumstances. We have previously shown that such rules are encoded in the lateral prefrontal cortex (PFC) and premotor cortex (PMC). Here, we extend these investigations to two other areas directly connected with the PFC and the PMC, the inferior temporal cortex (ITC) and the dorsal striatum (STR). Monkeys were trained to use two abstract rules: "same" or "different". They had to either hold or release a lever, depending on whether two successively presented pictures were the same or different, and depending on which rule was in effect. The rules and the behavioral responses were reflected most strongly and, on average, tended to be earlier in the PMC followed by the PFC and then the STR; few neurons in the ITC reflected the rules or the actions. By contrast, perceptual information (the identity of the pictures used as sample and test stimuli) was encoded more strongly and earlier in the ITC, followed by the PFC; they had weak, if any, effects on neural activity in the PMC and STR. These findings are discussed in the context of the anatomy and posited functions of these areas.     

Seizure-induced changes in neuropeptide Y-containing cortical neurons: Potential role for seizure threshold and epileptogenesis

Seizure activity induces transient changes in the levels of neuropeptide Y (NPY) and somatostatin (SS) in various brain regions, but it remains unclear whether this effect can persist for long periods and whether it is relevant to epileptogenesis. We report that brief seizures evoked by electroshock produced an increase in the number of NPY neurons in the dentate hilus and retrosplenial cortex, an effect that lasted 10 weeks. The number of hilar SS neurons remained unchanged. However, the pentylenetetrazole seizure threshold was somewhat decreased in electroshock-treated rats. Despite this, no spontaneous seizures were detected in this group. In contrast, status epilepticus (pilocarpine model) produced loss of the hilar NPY and SS cells. Moreover, all rats with status epilepticus showed spontaneous behavioral seizures and their seizure threshold was markedly decreased. These findings support the notion that sustained NPY overexpression induced by brief seizures can be important in preventing epileptogenesis.     

Seizure-induced changes in neuropeptide Y-containing cortical neurons: Potential role for seizure threshold and epileptogenesis

Seizure activity induces transient changes in the levels of neuropeptide Y (NPY) and somatostatin (SS) in various brain regions, but it remains unclear whether this effect can persist for long periods and whether it is relevant to epileptogenesis. We report that brief seizures evoked by electroshock produced an increase in the number of NPY neurons in the dentate hilus and retrosplenial cortex, an effect that lasted 10 weeks. The number of hilar SS neurons remained unchanged. However, the pentylenetetrazole seizure threshold was somewhat decreased in electroshock-treated rats. Despite this, no spontaneous seizures were detected in this group. In contrast, status epilepticus (pilocarpine model) produced loss of the hilar NPY and SS cells. Moreover, all rats with status epilepticus showed spontaneous behavioral seizures and their seizure threshold was markedly decreased. These findings support the notion that sustained NPY overexpression induced by brief seizures can be important in preventing epileptogenesis.     

Dynamic propagation of seizure discharges in the motor cortical kindling

Applying a multidimensional autoregressive model to an ictal discharge, a dynamic propagation of seizure discharge was investigated in cats kindled by motor cortical stimulations. By means of this method, the reactive discharge peculiar to each brain structure and projected activity could be separately described in terms of a new measure, i.e., power contribution which defines a degree of participation of each reactive activity in discharges at a given brain structure. The results showed that six phases could be distinguished during the process of generalization and that electrically induced discharge on the motor cortex might propagate as follows, first, a system including the ventral nuclei of the thalamus and perhaps the caudate nucleus are involved. After participation of more dorsal systems within homolateral brain structures, contralateral structures begin to participate in the generation of seizure discharges and finally become dominant in the maturated seizure.     

The role of the striatum in addiction

Addiction is a notorious treatment-resistant psychiatric disorder characterized by the impairment of self-monitoring, loss of interest in other targets of pleasure, and uncorrectable impulsive/compulsive drug-seeking behaviors. The striatum, particularly the ventral striatum (= the nucleus accumbens) is deeply involved in the acquisition and expression of addiction. Although only few pharmacotherapeutic approaches against addiction are available, the currently used animal models of addiction are sophisticated enough to mimic most of the representative phenotypes observed in human addicts. In addition, recent advances in neuroimaging techniques, such as positron emission tomography or functional magnetic resonance imaging, as well as computational neuroscience approaches have promoted our understanding of addiction, particularly at the circuitry level. In this review, I introduce some pivotal topics regarding addiction for discussion. First, I outline the updated concept regarding how dopamine is involved in addiction by focusing on 2 seemingly uncompromising hypotheses, prediction-error theory and incentive salience theory. Second, after providing a brief introduction to unmanageable maladaptive behaviors in addiction that may be attributable to the impairments of the medial prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex, I emphasize the roles of glutamatergic inputs projecting from these frontal areas to the nucleus accumbens in cue-primed reinstatement of drug-seeking and impaired neuronal plasticity. Third, on the basis of the complementary or counterbalancing relationship between goal-directed behaviors and habits, I discuss the foresights and pitfalls of the current concept of "addiction as a pathological habit." Lastly, I conclude my discussion with an integrated (but a rough) circuitry model of addiction.     

The role of nutrition in the development of evoked cortical responses in rat

Following lesions of varying size in different parts of the cerebral cortex in 24 adult cats the ensuing preterminal and terminal degeneration in the lateral reticular nucleus (nucleus of the lateral funiculus) has been studied by means of the Nauta silver impregnation method.The majority of cortical efferents terminating within the nucleus are derived from the anterior sigmoid gyrus. Scanty projections arise in the posterior sigmoid, the coronal and the anterior ectosylvian gyri. In addition some fibres are derived from the gyrus proreus and parts of the medial wall of the hemisphere below the cruciate sulcus. Evidence for fibres from the occipital, temporal, and parietal cortices and part of the cingulate gyrus was not obtained.The cortical fibres are distributed mainly to the nucleus contralateral to the lesion; only a few terminate in the ipsilateral nucleus. Regardless of the site of the lesion, if degeneration is present, it is found to be restricted to the rostrodorsal part of the magnocellular division of the lateral reticular nucleus. The subtrigeminal and the parvicellular divisions do not receive cortical afferents.Following small lesions placed in various parts of the sensorimotor cortex, no evidence in favour of a somatotopical organization of the projection was found.Only few degenerating fragments are seen close to the soma of the cells, indicating that that most synaptic contacts are presumably axodendritic.The sites of origin of the cortical projection to the lateral reticular nucleus are discussed with reference to present knowledge about the functional and cytoarchitectonic localization within the cerebral cortex and other corticofugal fibre tracts. The area of termination of the cortical fibres overlaps to some extent with the terminal areas of other afferents to the nucleus (from the spinal cord, the red nucleus and the fastigial nucleus).From a functional point of view it is of interest that the cortical fibres to the red nucleus are derived from the same regions as those to the lateral reticular nucleus. Even if the fibres to the latter from the red nucleus have a somewhat different area of termination within the magnocellular division, both connections (the direct corticoreticular and the cortico-rubro-reticular) may serve as links in a cerebro-cerebellar pathway. However, both projections may also be imagined to influence the spinal input to the cerebellum via the lateral reticular nucleus.     

Topography of cocaine-induced gene regulation in the rat striatum: relationship to cortical inputs and role of behavioural context

Psychostimulants alter gene expression in projection neurons of the striatum, and such neuroplasticity is implicated in drug addiction and dependence. Evidence indicates that excitatory inputs from the cortex and thalamus are critical for these molecular changes. In the present study, we determined the topography of cocaine-induced changes in gene expression in the rat striatum and investigated whether these molecular alterations are associated with particular cortical inputs. Acute induction of c-fos (by 25 mg/kg of cocaine), and the c-fos response and dynorphin expression after repeated cocaine treatment (25 mg/kg, 4 days) were assessed as examples for short-term and longer-term molecular changes, respectively. In addition, we examined whether these molecular effects were influenced by the behaviour performed during cocaine action (running-wheel training vs. open field). Our results demonstrate that the overall topography of cocaine-induced gene regulation in the striatum is remarkably stable. Both acute and longer-term molecular changes were maximal in caudal dorsal striatal sectors that receive convergent inputs from the medial agranular and the sensorimotor cortex. In contrast, relatively minor or no effects were found in rostral and ventral striatal sectors. However, running-wheel training under the influence of cocaine enhanced the c-fos response to a subsequent cocaine challenge selectively in parts of the caudal sensorimotor striatum. These results indicate that cocaine produces molecular adaptations preferentially in cortico-basal ganglia circuits through the sensorimotor striatum, and that some of these neuronal changes are influenced by the behaviour performed during drug exposure.     

Anatomical evidence for cortical projections from the striatum in the cat

Several anatomical and physiological studies have thus far failed to confirm the existence of striatocortical projections proposed in 1895 by Cajal. Evidence for such striatocortical projections was obtained in the present study using the horseradish peroxidase (HRP) tracing method. When 0.1–0.8 μ1 of 30–50% HRP in saline was injected into different cortical regions in cats, HRP was transported to cells in different thalamic nuclei, striatum and the globus pallidus. Only large striatal cells, 30–60 μm in their long axes, contained HRP reaction product. After injection in area AI, the striatocortical cells were located in the dorsal parts of the middle third of putamen, where auditory cortical afferents are known to project, thereby suggesting reciprocal connections between the cerebral cortex and the striatum.     

Ventral premotor to primary motor cortical interactions during object-driven grasp in humans

Interactions between the ventral premotor (PMv) and the primary motor cortex (M1) are crucial for transforming an object's geometrical properties, such as its size and shape, into a motor command suitable for grasp of the object. Recently, we showed that PMv interacts with M1 in a specific fashion, depending on the hand posture. However, the functional connectivity between PMv and M1 during the preparation of an actual grasp is still unknown.To address this issue, PMv-M1 interactions were tested while subjects were preparing to grasp different visible objects requiring either a precision grip or a whole hand grasp. A conditioning-test transcranial magnetic stimulation (TMS) paradigm was used: a test stimulus was applied over M1 either in isolation or after a conditioning stimulus delivered, at different delays, over the ipsilateral PMv. Motor evoked potentials (MEPs) were recorded in the first dorsal interosseus and abductor digiti minimi muscles, which show highly differentiated activity according to grasp.While subjects prepared to grasp, delivering a conditioning PMv pulse 6 or 8 msec before a test pulse over M1 strikingly facilitated MEPs in the specific muscles that were used in the upcoming grasp. This degree of facilitation correlated with the amount of muscle activity used later in the trial to grasp the objects.The present results demonstrate that, during grasp preparation, the PMv-M1 interactions are muscle-specific. PMv appears to process the object geometrical properties relevant for the upcoming grasp, and transmits this information to M1, which in turn generates a motor command appropriate for the grasp. We also reveal that the grasp-specific facilitation resulting from PMv-M1 interactions is differently related to the upcoming grasp muscle activity than is that from paired-pulse stimulation over M1, suggesting that these two TMS paradigms assess the excitability of cortico-cortical pathways devoted to the control of grasp at two different levels.     

Localization of gliosis in the corpus striatum of mice following cortical lesions

Localized lesions of the medial and lateral frontal cortex were used to study gliosis, neurofilament content and changes in synaptic density in the mouse striatum. Relationships between the sites of cortical lesions and the localization of changes in different regions of the striatum were examined after 3 and 12 weeks. Independent of the location of frontal cortex lesions, glial fibrillary acidic protein (GFAP) immunoreactivity was increased throughout the entire striatum after 3 weeks. Twelve weeks after lesioning, increases in GFAP were confined to the dorsomedial (DM) striatum following medial cortical lesions, and to the dorsolateral (DL) striatum following lateral cortical lesions, suggesting persistent gliosis only in areas of striatal deafferentation. It appears, therefore, that the mechanisms which induce gliosis after short and long time periods are different.