Cortico-Subcortical Re-Entrant Circuit

Synonyms

Basal ganglia-thalamocortical circuit; Cortical-basal ganglia circuit; Basal ganglia-thalamocortical loop

Definition

Cortico-subcortical re-entrant circuits are composed of a series of connections that start in a particular part of the cerebral cortex and lead via subsequent steps in the basal ganglia and the thalamus back to the same part of the cortex. More in particular, cytoarchitectonically and functionally distinct cortical areas in the frontal lobe form the focal point of these circuits. Each frontal cortical area projects to a specific region of the striatum and that striatal region projects via the globus pallidus or substantia nigra to a particular thalamic nucleus or part thereof. This part of the thalamus, in turn, is in reciprocal connection with the original frontal cortical area, closing the circuit (Fig. 1).

Cortico-Subcortical Re-Entrant Circuit. Figure 1

Basic diagram of the architecture of cortico-subcortical re-entrant circuits that involve the different areas of the frontal cortex, the basal ganglia (gray boxes) and the thalamus.

These cortico-subcortical re-entrant circuits are also being indicated as the basal ganglia-thalamocortical circuits. Three “families” of cortico-subcortical re-entrant circuits have been described: sensory-motor, complex or cognitive and limbic or emotional-motivational circuits. The recognition of this circuitous arrangement between the cerebral cortex, basal ganglia and thalamus has had great impact on our understanding of the neuronal substrate of forebrain functions and the pathophysiological basis of various neurological and psychiatric disorders.

Characteristics

The connectional relationships between the cerebral cortex and the basal ganglia have been viewed in various ways in the past. Whereas initially it was thought that the basal ganglia send their output directly to lower brain structures such as the brainstem and spinal cord, Nauta and Mehler [1] showed that the basal ganglia mainly project to the thalamus. As a consequence, the influence of the basal ganglia reaches the cerebral cortex since the thalamus is reciprocally connected with the cortex. However, at that time the prevailing idea was that the basal ganglia, which themselves receive inputs from the cortex of the entire hemisphere, by subsequent steps of convergence, mainly direct their influence via the ventral anterior thalamic nucleus to the premotor cortex. In other words, the basal ganglia were considered to collect and integrate information from all functionally different cortical areas and direct their output via the thalamus to motor-related cortical areas, the basal ganglia in essence having an influence on the motor system. A major breakthrough was established with the landmark paper by Alexander and colleagues [2] who, on the basis of a reinterpretation of already existing neuroanatomical and electrophysiological data, proposed that the connections between the cerebral cortex, basal ganglia and thalamus are arranged in parallel, functionally segregated basal ganglia-thalamocortical loops or circuits. It became then generally accepted that, next to the premotor cortex, also extensive parts of the prefrontal cortex are under the influence of the basal ganglia and form part of cortico-subcortical re-entrant circuits. As a consequence, premotor and prefrontal cortices together with connectionally related parts of the basal ganglia and thalamus form a series of parallel, partially closed circuits that subserve a wide range of motor, behavioral en emotional-motivational functions.

Architecture of the Cortico-Subcortical Re-Entrant Circuits

The more detailed architecture of cortico-subcortical re-entrant circuits is as follows. Architectonically and functionally distinct frontal cortical areas form the starting and re-entrant point of the basal ganglia-thalamocortical circuits [2,3]. The projections from the cerebral cortex to the striatum are highly topographically organized. Motor and premotor, including oculomotor cortical areas project to the dorsal and lateral parts of the caudate nucleus and putamen. Dorsolateral prefrontal cortical areas, involved in executive functions and working memory, project to intermediate, more ventrally located regions of the caudate-putamen complex. Finally, medial and orbital prefrontal areas, involved in emotional and motivational processes, project to the most ventral and medial parts of the striatum, including the nucleus accumbens (Fig. 2).

Cortico-Subcortical Re-Entrant Circuit. Figure 2

Schematic representation of the organization of the corticostriatal projections in rats. At the left hand side different motor and prefrontal cortical regions in the frontal lobe are represented in different colors. The projections to the striatum at the right hand side are highly topographically organized providing for functionally different sectors in the striatum related to different cortical areas represented in the same color. Even though there is a distinct topography in the corticostriatal projections, there also exists overlap between the different projection areas. Abbreviations of the various prefrontal cortical areas in the rat: ACd, dorsal anterior cingulate area; AId, dorsal agranular insular area; AIv, ventral agranular insular area, IL, infralimbic area; PLd, dorsal prelimbic area; PLv, ventral prelimbic area. Core and shell are distinct subregions of the nucleus accumbens in the ventral striatum.

This corticostriatal topography forms the basis for three “families” of cortical basal ganglia-thalamocortical circuits, each consisting of several sub-circuits, that subserve sensory-motor, complex or cognitive and emotional-motivational behavioral functions. Next to these cortical inputs from the frontal lobe, the striatum receives projections from other cerebral cortical areas in more caudal parts of the hemisphere (parietal, occipital and temporal lobes), limbic structures, such as the amygdala and hippocampus, midline and intralaminar thalamic nuclei and the dopaminergic and serotonergic system. The striatum has therefore been designated as the input structure of the basal ganglia. Via different routes, the functionally different striatal regions reach distinct parts of the internal segment of the globus pallidus, the reticular part of the substantia nigra or the ventral pallidum that together form the output structures of the basal ganglia. These structures, in parallel, project to different thalamic nuclei that are in reciprocal contact with the original frontal cortical areas. Thus, the internal segment of the globus via specific parts of the ventral lateral and ventral anterior thalamic nuclei projects back to the premotor cortex, closing the so-called motor loop. The reticular part of the substantia nigra projects via specific parts of the ventral anterior and mediodorsal thalamic nuclei back to dorsolateral prefrontal areas, closing the so-called complex or cognitive loop. Finally, the ventral pallidum projects primarily to the mediodorsal thalamic nucleus which is connected to the medial and orbital prefrontal areas, closing the so-called limbic loop.

In the previous paragraph the basic architecture of the closed cortico-subcortical re-entrant circuits has been depicted. There are at least three aspects that are of interest in the context of our understanding of the structural and functional significance of these circuits.

First, the input and output structures of the basal ganglia are interconnected via two routes that have opposing effects on the basal ganglia output. The above-described striatal projections to the internal segment of the globus pallidus, the reticular part of the substantia nigra and the ventral pallidum from part of the so-called direct striatopallidal output pathway. The second, so-called indirect striatopallidal output pathway leads via subsequent synaptic interruptions in the external segment of the globus pallidus and the subthalamic nucleus to the basal ganglia output structures [3,4]. Stimulation of the direct pathway at the level of the striatum leads to a higher activity, stimulation of the indirect pathway to a lower activity at the level of the thalamocortical projections within a particular circuit. Interestingly, the direct and indirect striatal output pathways are modulated by dopamine D1 and D2 receptors, respectively. The direct pathway has been shown to facilitate, the indirect pathway to inhibit the expression of motor, cognitive and emotional behavioral output [4]. For normal functioning, a balance between the two output pathways is thought to be essential. Striatal dopamine levels have a strong influence on this balance, low levels leading to paucity and high levels to an excess of simple movements or complex behavioral output. The just described organization of the connections within a particular basal ganglia-thalamocortical circuit forms the neuronal basis for what is considered the basic function of the basal ganglia in relation to the cerebral cortex, i.e. the selection of an appropriate motor, cognitive or emotional behavioral output in a particular context [5].

Second, it is very likely that the contextual information necessary for such selection mechanisms that take place within the basal ganglia-thalamocortical circuits enters these circuits at the level of the striatum. Various cortical areas in the parietal, occipital and temporal lobes project in a topographical way to the striatum where they converge with functionally and connectionally related corticostriatal projections from the frontal lobe. For example, the ventral and medial parts of the striatum that form the limbic loop starting in the medial and orbital prefrontal areas receive information from the hippocampus and amygdala. These two limbic structures feed information about the mnemonic and emotional aspects of the context in which a behavioral program must be selected. Interestingly, the hippocampus and amygdala not only project to the striatum, but also to the prefrontal cortical area that is the origin of the corticostriatal projections to the same part of the striatum. Similar arrangements exist for the projections of the midline and intralaminar thalamic nuclei to different parts of the striatum and frontal cortical areas (Fig. 3).

Cortico-Subcortical Re-Entrant Circuit. Figure 3

Schematic representation in a midsagittal view of the rat brain of a cortical-subcortical re-entrant loop (black, stippled arrows) involving the prefrontal cortex, the mediodorsal thalamus and the ventral parts of the basal ganglia. In addition, the relationship of the projections of the midline thalamic nuclei and the amygdala with this loop are represented in this scheme (red arrows). The organization is as follows. Distinct basal amygdaloid subnuclei project to restricted parts of the prefrontal cortex and the ventral striatum that are both part of the same cortical-subcortical re-entrant loop. Likewise, distinct nuclei of the midline and intralaminar thalamic complex project to prefrontal cortical and ventral striatal areas that in turn are interconnected. In addition, the midline nuclei project to that part of the basal amygdala that is related to the same loop. This scheme represents a cortical-subcortical circuit that involves the medial prefrontal cortex, the ventral striatum and the medial segment of the mediodorsal thalamic nucleus. Similar arrangements exist for the relationships of midline/intralaminar thalamic nuclei and basal amygdaloid nuclei with other cortical-subcortical re-entrant circuits. Abbreviations: ac, anterior commissure; ACv, ventral anterior cingulate area; BAm, basal amygdaloid nucleus; FR2, frontal area 2; GPe, external segment of the globus pallidus; MDm, medial segment of the mediodorsal thalamic nucleus; MO, medial orbital area; IL, infralimbic area; PFCmed, medial prefrontal cortex; PC, posterior cingulate area; PL, prelimbic area; PV, paraventricular thalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STh, subthalamic nucleus; VP, ventral pallidum; VStr, ventral striatum; Core and shell are distinct subregions of the nucleus accumbens in the ventral striatum.

The midline and intralaminar receive primarily inputs from brainstem nuclei and are likely to determine the level of activity of individual basal ganglia-thalamocortical circuits [6]. The specific arrangements of cortical, limbic and thalamic inputs into basal ganglia-thalamocortical loops suggests that these circuits form part of larger distributed circuits that are involved in particular motor and behavioral functions.

Third, whereas the closed nature of the cortico-subcortical circuits has been emphasized, it is clear that there exist connections between these circuits that provide ways by which limbic and cognitive circuits might ultimately influence motor circuits. Indeed an ascending spiral of connections from limbic to motor circuits has been suggested on the basis striato-pallido-thalamic projections that shift from one loop to the other [7]. Likewise an ascending spiral from limbic via cognitive to motor loops has been described through the dopaminergic system [8]. Such arrangements of interconnections between circuits might form the basis for the gradual shift from unconditioned behaviors to conditioned behaviors to, finally, habit formation in the course of a behavioral learning process.

Clinical Relevance

The recognition of the cortico-subcortical re-entrant circuits and the realization that these circuits subserve the wide range of sensory-motor to cognitive and emotional-motivational functions has had great impact on the interpretation and understanding of the pathophysiological basis of several neurological and psychiatric diseases [9,10]. Thus, disturbances of way stations of the dorsally located motor circuit lead to classical neurological symptoms [9]. An example is Parkinson’s disease in which the clinical signs of bradykinesia, rigidity and tremor are associated with a degeneration of the dopaminergic innervation of the dorsolateral, sensory-motor related part of the striatum (mainly putamen). Disturbances in cortical and basal ganglia way stations of the cognitive or complex loop (centered on the dorsolateral prefrontal cortex) are associated with executive function deficits (e.g. schizophrenia). Finally, disturbances of one or more way stations in the limbic cortico-subcortical re-entrant circuit has been associated with various other psychiatric disorders such as substance abuse, obsessive-compulsive disorder or mood disturbances like apathy.