A hypothetical role of cortico-basal ganglia-thalamocortical loops in visual processing

The goal of the present work was to define the mechanisms underlying the contribution of sensory and limbic cortico-basal ganglia-thalamocortical loops to visual processing and its attentional modulation. We proposed that visual processing is promoted by dopamine-dependent long-term modifications of synaptic transmission in the basal ganglia that favour a selection of neocortical patterns representing a visual stimulus. This selection is the result of the opposite sign of modulation of strong and weak cortico-basal ganglia inputs and subsequent activity reorganization in each loop. Reorganization leads to disinhibition/inhibition of cortical neurons strongly/weakly excited by stimulus during dopamine release. Recruitment of the thalamo-basal ganglia-collicular pathway is proposed to be necessary for stimulus-evoked dopamine release that underlies bottom-up attentional effects. Visual excitation of the prefrontal cortex and hippocampus (via the thalamus), their cooperation in control of the basal ganglia and dopaminergic cell firing, and simultaneous modulation of activity in diverse cortico-basal ganglia-thalamocortical loops is proposed to underlie top-down attentional effects. It follows from our model that only those components of cortical responses can be modulated by attention, whose onset exceeds the latency of visual responses of dopaminergic cells (50-110 ms). This and other consequences of the model are in accordance with known experimental data.     

A contribution of synaptic plasticity in the basal ganglia to processing of visual information

The mechanism of involvement of the basal ganglia in processing of visual information on the basis of dopamine-dependent modulation of efficacy of synaptic transmission in interconnected parallel associative and limbic loops (cortex--basal ganglia--thalamus--cortex) is proposed. Each loop consists of one of the visual or prefrontal cortical areas connected with the thalamic nucleus and corresponding loci in different nuclei of the basal ganglia. Circulation of activity in such a loop provides reentrance of information into the thalamus and neocortex. Dopamine releasing in response to a visual stimulus oppositely modulates the efficacy of "strong" and "weak" corticostriatal inputs. Subsequent reorganization of activity in the loop leads to a disinhibition (inhibition) of activity of those cortical neurons that were "strongly" ("weakly)" excited by the visual stimulus simultaneously with activation of dopaminergic cells. A selected neuronal pattern in each cortical area represents a property of the visual stimulus processed by this area. Excitation of dopaminergic cells by the visual stimulus via the superior colliculi requires parallel activation of a disinhibitory input to the superior colliculi via the thalamus and a "direct" pathway through the basal ganglia. The prefrontal cortex excited by the visual stimulus via the mediodorsal thalamic nucleus performs a top-down control over the dopaminergic cell activity, supervising simultaneous dopamine release in different striatal loci and thus promotes the interconnected selection of neuronal representations of individual properties of the visual stimulus and their binding in an integrated image.     

Generation of Ponto-Geniculo-Occipital (PGO) waves as a possible reason of disturbances in visual perception in microsleep

A hypothesis is put forward that one of the reasons for disturbances in visual perception during microsleep could be a spontaneous generation of Ponto-Geniculo-Occipital (PGO) waves. If the PGO waves are generated in microsleep, they could propagate into different thalamic nuclei conveying visual infomation. Consequently, a propagation of visual infonnation from the retina (if the eyes are opened) to visual neocortical areas and to input basal ganglia nucleus, striatum could be impaired. According to previously proposed mechanism of visual processing, which includes visual attention, in absence of striatum activation by a visual stimulus, a disinhibition through the basal ganglia of superior colliculus that transfer visual information to dopaminergic structures becomes impossible. Due to absence of dopamine release in response to visual stimulus, the attention to this stimulus cannot start, and therefore its processing worsens in all visual cortical areas. The suggested hypothesis could be verified in experiments with artificially evoked microsleep using non-invasive methods for searching for the correlates of the PGO activity presence in the brain.     

Role of the basal ganglia in the occurrence of paradoxical sleep dreams (hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in the occurrence of paradoxical sleep dreams and rapid eye movements is proposed. According to this mechanism, paradoxical sleep is provided by facilitation of activation of cholinergic neurons in the pedunculopontine nucleus as a result of suppression of their inhibition from the output basal ganglia nuclei. This disinhibition is promoted by activation of dopaminergic cells by pedunculopontine neurons, subsequent rise in dopamine concentration in the input basal ganglia structure. striatum, and modulation of the efficacy of cortico-striatal inputs. In the absence of signals from retina, a disinhibition of neurons in the pedunculopontine nucleus and superior colliculus allows them to excite neurons in the lateral geniculate body and other thalamic nuclei projecting to the primary and higher visual cortical areas, prefrontal cortex and back into the striatum. Dreams as visual images and "motor hallucinations" are the result of an increase in activity of definitely selected groups of thalamic and neocortical neurons. This selection is caused by modifiable action of dopamine on long-term changes in the efficacy of synaptic transmission during circulation of signals in closed interconnected loops, each of which includes one of the visual cortical areas (motor cortex), one of the thalamic nuclei, limbic and one of the visual areas (motor area) of the basal ganglia. pedunculopontine nucleus, and superior colliculus. Simultaneous modification and modulation of synapses in diverse units of neuronal loops is provided by PGO waves. Disinhibition of superioir colliculus neurons and their excitation by pedunculopontine nucleus lead to an appearance of rapid eye movements during paradoxical sleep.     

The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. II. Mechanism of synergistic modulation of thalamic activity via the direct and indirect pathways through the basal ganglia

A possible mechanism underlying the modulatory role of dopamine, adenosine and acetylcholine in the modification of corticostriatal synapses, subsequent changes in signal transduction through the "direct" and "indirect" pathways in the basal ganglia and variations in thalamic and neocortical cell activity is proposed. According to this mechanism, simultaneous activation of dopamine D1/D2 receptors as well as inactivation of adenosine A1/A(2A) receptors or muscarinic M4/M1 receptors on striatonigral/striatopallidal inhibitory cells can promote the induction of long-term potentiation/depression in the efficacy of excitatory cortical inputs to these cells. Subsequently augmented inhibition of the activity of inhibitory neurons of the output nuclei of the basal ganglia through the "direct" pathway together with reduced disinhibition of these nuclei through the "indirect" pathway synergistically increase thalamic and neocortical cell firing. The proposed mechanism can underlie such well known effects as "excitatory" and "inhibitory" influence of dopamine on striatonigral and striatopallidal cells, respectively; the opposite action of dopamine and adenosine on these cells; antiparkinsonic effects of dopamine receptor agonists and adenosine or acetylcholine muscarinic receptor antagonists.     

A role of the basal ganglia in the occurrence of visual hallucinations (a hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in visual hallucinations is proposed. According to this mechanism, hallucination is the result of modulation of the efficacy of corticostriatal synaptic inputs and changes in spiny cell activity due to the rise of striatal dopamine concentration (or due to other reasons). These changes cause an inhibition of neurons in the substantia nigra pars reticulata and subsequent disinhibition of neurons in the superior colliculus and pedunculopontine nucleus (including its cholinergic cells). In the absence of afferentation from the retina this disinhibition leads to activation of neurons in the lateral geniculate nucleus, pulvinar and other thalamic nuclei projecting to the primary and highest visual cortical areas, prefrontal cortex, and also back to the striatum. Hallucinations as conscious visual patterns are the result of selection of signals circulating in several interconnected loops each of which includes one of above mentioned neocortical areas, one of thalamic nuclei, limbic and one of visual areas of the basal ganglia, superior colliculus and/or pedunculopontine nucleus. According to our model, cannabinoids, opioids and ketamine may lead to hallucinations due to their promotional role in the LTD of cortical inputs to GABAergic spiny cells of striatal striosomes projecting to dopaminergic neurons, disinhibition of the lasts, and increase in striatal dopamine concentration.     

Possible mechanisms of involvement of the subthalamic nucleus and structures interconnected with this nucleus in movement disorders evoked by dopamine depletion

A possible mechanism of involvement of the subthalamic nucleus (STN) in movement disorders evoked by dopamine deficit is suggested. Multifunctional role of the STN is based on following reasons. Various STN cells participate in the cortico-basal ganglia-thalamocortical loop and in the basal ganglia-pedunculopontine-basal ganglia loop. Complexity of neural circuits is determined by functional heterogeneity of neurons in the nuclei, reciprocally connected with the STN, as well as by opposite modulation of activity of these neurons by dopamine due to activation of different types of pre- and postsynaptic receptors. Dopamine influences activity of STN neurons directly, through pre- and postsynaptic receptors. It is assumed that high-frequency stimulation of the STN can reduce or eliminate Parkinsonian symptoms not only owing to inhibition of activity of GABAergic neurons in the output basal ganglia nuclei, projected into the thalamus or pedunculopontine nucleus, but also due to excitation of glutamatergic or cholinergic neurons in the output nuclei, and due to potentiation of excitatory inputs to preserved dopaminergic neurons and subsequent rise in dopamine concentration.     

A possible mechanism of dopamine-induced synergistic disinhibition of thalamic cells via "direct" and "indirect" pathways in basal ganglia

On the basis of the mechanism of synaptic plasticity that we have earlier suggested for striatal spiny neurons and with regard to the known data about the predominance of dopamine-sensitive D1/D2 receptors on the striatonigral/striatopallidal cells it is hypothesized that the induction of the long-term potentiation/depression of the efficacy of excitatory cortical inputs to these cells can underlie the excitatory/inhibitory effect of dopamine on the activity of neurons that originate the "direct"/"indirect" pathways through the basal ganglia. Both these effects will lead to an enhancement of the activity of thalamic cells and activity of the efferent neocortical neurons excited by thalamic cells. The long-term potentiation of corticostriatal inputs to striosomal neurons, where, predominantly, D1 receptors are located, can also be induced by dopamine. This effect can be responsible of a rise of inhibition of dopaminergic cells and decrease in dopamine release by these cells. Such an event sequence can provide a stable dopamine concentration in the loop neocortex-basal ganglia-thalamus-neocortex.     

Role of dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo---hippocampal loop in response decrement

The mechanism of response decrement in hippocampal and dopaminergic neurons on repeating stimuli based on the dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo--hippocampal loop is suggested. Activation of hippocampal neurons caused by new stimulus facilitates occurrence of reaction of dopaminergic cells due to their disinhibition through striatopallidal cells of nucleus accumbens and ventral pallidum. However, increase in dopamine level and activation accumbens and ventral pallidum. However, increase in dopamine level and activation of D2 receptors on the striatopallidal cell, while promoting depression of hippocampal inputs, prevents disinhibition of dopaminergic cells, and their reactions start their decrement. The subsequent decrease in D1 receptor activation leads to reduction of efficiency of neuron excitation in the hippocampal CA1 fields, as well as in striatonigral cells of nucleus accumbens. This leads to a decrease of disinhibition through a direct pathway via the basal ganglia of thalamic nucleus reunions which activates neurons of the CA1 field. This effect causes decrement of reactions of the hippocampal neurons, a subsequent reduction of dopaminergic cell disinhibition, and further decrement of their responses.     

A possible mechanism of participation of neuronal loops cortex - basal ganglia - thalamus - cortex in time perception

A mechanism of time perception is suggested. It is based on a postulate that time when stimulus arrives (parameter "when") is such property of stimulus as its physical properties (parameters "what"), and association "what - when" is perceived in those area of neocortex in which property "what" is processed after its repeated excitation. The time of repeated excitation which determines clock rate of "intrinsic clock", depends on dopamine influence at functioning of the cortico - basal ganglia - thalamocortical loop that promotes contrasted amplification of activity of cortical neurones, firstly activated by stimulus. Accumulation of time counts is performed in the neocortex and coded by the number of neuronal discharges. Duration of current interval is proportional to the number and duration of cycles of repeated neocortical excitation. Time counting can be started involuntary by stimulus, or voluntary due to activation of prefrontal cortex. The mechanism of time perception is similar for stimuli of different modalities owing to resemblance of functioning of topically organised cortico - basal ganglia - thalamocortical loops, it follows from our model that the more (less) concentration of dopamine in the striatumm the higher (low) clock rate, so the real interval will be estimated more (less) precisely and perceived as longer (short). These consequences of the model are in accordance with known experimental data.     

The early topography of thalamocortical projections is shifted in Ebf1 and Dlx1/2 mutant mice

The prevailing model to explain the formation of topographic projections in the nervous system stipulates that this process is governed by information located within the projecting and targeted structures. In mammals, different thalamic nuclei establish highly ordered projections with specific neocortical domains and the mechanisms controlling the initial topography of these projections remain to be characterized. To address this issue, we examined Ebf1(-/-) embryos in which a subset of thalamic axons does not reach the neocortex. We show that the projections that do form between thalamic nuclei and neocortical domains have a shifted topography, in the absence of regionalization defects in the thalamus or neocortex. This shift is first detected inside the basal ganglia, a structure on the path of thalamic axons, and which develops abnormally in Ebf1(-/-) embryos. A similar shift in the topography of thalamocortical axons inside the basal ganglia and neocortex was observed in Dlx1/2(-/-) embryos, which also have an abnormal basal ganglia development. Furthermore, Dlx1 and Dlx2 are not expressed in the dorsal thalamus or in cortical projections neurons. Thus, our study shows that: (1) different thalamic nuclei do not establish projections independently of each other; (2) a shift in thalamocortical topography can occur in the absence of major regionalization defects in the dorsal thalamus and neocortex; and (3) the basal ganglia may contain decision points for thalamic axons' pathfinding and topographic organization. These observations suggest that the topography of thalamocortical projections is not strictly determined by cues located within the neocortex and may be regulated by the relative positioning of thalamic axons inside the basal ganglia.     

A possible mechanism of participation of dopaminergic cells and striatal cholinergic interneurons in the conditioned selection of motor activity

A possible mechanism of participation of cholinergic striatal interneurons and dopaminergic cells in conditioned selection of a certain types of motor activity is proposed. This selection is triggered by simultaneous increase in the activity of dopaminergic cells and a pause in the activity of cholinergic interneurons in response to a conditioned stimulus. This pause is promoted by activation of striatal inhibitory interneurons and action of dopamine at D2 receptors on cholinergic cells. Opposite changes in dopamine and acetylcholine concentration synergistically modulate the efficacy of corticostriatal inputs, modulation rules for the "strong" and "weak" corticostriatal inputs are opposite. Subsequent reorganization of neuronal firing in the loop cortex--basal ganglia--thalamus--cortex results in amplification of activity of the group of cortical neurons that strongly activate striatal cells, and simultaneous suppression of activity of another group of cortical neurons that weakly activate striatal cells. These changes can underlie a conditioned selection of motor activity performed with involvement of the motor cortex. As follows from the proposed model, if the time delay between conditioned and unconditioned stimuli does not exceed the latency of responses of dopaminergic and cholinergic cells (about 100 ms), conditioned selection of motor activity and learning is problematic.     

Reward-dependent gain and bias of visual responses in primate superior colliculus

Eye movements are often influenced by expectation of reward. Using a memory-guided saccade task with an asymmetric reward schedule, we show that visual responses of monkey SC neurons increase when the visual stimulus indicates an upcoming reward. The increase occurred in two distinct manners: (1) reactively, as an increase in the gain of the visual response when the stimulus indicated an upcoming reward; (2) proactively, as an increase in anticipatory activity when reward was expected in the neuron's response field. These effects were observed mostly in saccade-related SC neurons in the deeper layer which would receive inputs from the cortical eye fields and the basal ganglia. These results, together with recent findings, suggest that the gain modulation may be determined by the inputs from both the cortical eye fields and the basal ganglia, whereas the anticipatory bias may be derived mainly from the basal ganglia.     

Attention-related,cross-modality modulation of somatosensory neurons in primate ventrobasal (VB) thalamus

Attention-related modulation (AM) of the somatosensory responses of single neurons has been demonstrated in the cerebral cortex and medullary dorsal horn, but not in the ventrobasal thalamus. The somatically evoked activity was recorded of single units in the ventral posterior lateral thalamus (VPL) of awake monkeys while they detected the termination of task-relevant somatic or visual stimuli. Eighteen of 56 somatically responsive VPL neurons are reported that were recorded for enough time for a complete analysis of their responses during both the visual and somatic attention tasks. All neurons were spontaneously active and responded either to innocuous cutaneous (13/18) or deep (5/18) stimuli. Seven neurons (7/18, 38.8%) showed AM of somatosensory responsiveness. Two cells (2/7, 28.6%) showed AM only during the visual task, two others (2/7, 28.6%) only during the somatosensory task, and three cells (3/7, 42.8%) showed AM during both tasks. All five cells showing AM during the somatosensory task had enhanced responses to the task-relevant somatic stimulus. In contrast, the somatosensory responses of all five cells showing AM during the visual task were reduced. It is concluded that selective attention is associated with a modality specific modulation of the somatosensory responses of a sub-population of neurons within the primate VPL nucleus.     

Unitary IPSPs drive precise thalamic spiking in a circuit required for learning

Song learning in birds requires a basal ganglia-thalamo-pallial loop that contains a calyceal GABAergic synapse in the thalamus. Information processing within this circuit is critical for proper song development; however, it is unclear whether activation of the inhibitory output of the basal ganglia structure Area X can drive sustained activity in its thalamic target, the medial portion of the dorsolateral thalamic nucleus (DLM). We show that high-frequency, random activation of this GABAergic synapse can drive precisely timed firing in DLM neurons in brain slices in the absence of excitatory input. Complex IPSP trains, including spike trains recorded in vivo, drive spiking in slices with high reproducibility, even between animals. Using a simple model, we can predict much of DLM's response to natural stimulus trains. These data elucidate basic rules by which thalamic relay neurons translate IPSPs into suprathreshold output and demonstrate extrathalamic GABAergic activation of thalamus.     

Potential mechanisms of effects of endogenous neuromodulators on the interdependent activity of neurons in various nuclei of the basal ganglia

A possible mechanism of influence of neuromodulators on interdependent activity of neurons in the diverse basal ganglia nuclei is suggested. According to modulation rules, an activation of postsynaptic Gs- or Gq/11-(Gi/0-) protein coupled receptors promotes induction of long-term potentiation (depression) of excitatory inputs to different neurons and augmentation (lowering) of their activity; an activation of presynaptic Gs- or Gq/11-(Gi/0-) protein coupled receptors promotes a rise (decrease) of release of GABA and co-peptides from striatal terminals and glutamate release from subthalamic terminals in the globus pallidus and output nuclei. It follows from the modulation rules that, since identical receptors are present on striatal neuron and their axon terminals, effects of neuromodulator action in diverse basal ganglia nuclei can be summarized. Neuromodulators released from striato-nigral and striato-pallidal fibers could promote interdependent activity of neurons in "direct" and "indirect" pathways through the basal ganglia due to convergence of these fibers on cholinergic interneurons and pallido-striatal cells.     

Attention-related, cross-modality modulation of somatosensory neurons in primate ventrobasal (VB) thalamus

Attention-related modulation (AM) of the somatosensory responses of single neurons has been demonstrated in the cerebral cortex and medullary dorsal horn, but not in the ventrobasal thalamus. The somatically evoked activity was recorded of single units in the ventral posterior lateral thalamus (VPL) of awake monkeys while they detected the termination of task-relevant somatic or visual stimuli. Eighteen of 56 somatically responsive VPL neurons are reported that were recorded for enough time for a complete analysis of their responses during both the visual and somatic attention tasks. All neurons were spontaneously active and responded either to innocuous cutaneous (13/18) or deep (5/18) stimuli. Seven neurons (7/18, 38.8%) showed AM of somatosensory responsiveness. Two cells (2/7, 28.6%) showed AM only during the visual task, two others (2/7, 28.6%) only during the somatosensory task, and three cells (3/7, 42.8%) showed AM during both tasks. All five cells showing AM during the somatosensory task had enhanced responses to the task-relevant somatic stimulus. In contrast, the somatosensory responses of all five cells showing AM during the visual task were reduced. It is concluded that selective attention is associated with a modality specific modulation of the somatosensory responses of a sub-population of neurons within the primate VPL nucleus.     

A dynamical model for the basal ganglia-thalamo-cortical oscillatory activity and its implications in Parkinson’s disease

We propose to investigate brain electrophysiological alterations associated with Parkinson’s disease through a novel adaptive dynamical model of the network of the basal ganglia, the cortex and the thalamus. The model uniquely unifies the influence of dopamine in the regulation of the activity of all basal ganglia nuclei, the self-organised neuronal interdependent activity of basal ganglia-thalamo-cortical circuits and the generation of subcortical background oscillations. Variations in the amount of dopamine produced in the neurons of the substantia nigra pars compacta are key both in the onset of Parkinson’s disease and in the basal ganglia action selection. We model these dopamine-induced relationships, and Parkinsonian states are interpreted as spontaneous emergent behaviours associated with different rhythms of oscillatory activity patterns of the basal ganglia-thalamo-cortical network. These results are significant because: (1) the neural populations are built upon single-neuron models that have been robustly designed to have eletrophysiologically-realistic responses, and (2) our model distinctively links changes in the oscillatory activity in subcortical structures, dopamine levels in the basal ganglia and pathological synchronisation neuronal patterns compatible with Parkinsonian states, this still remains an open problem and is crucial to better understand the progression of the disease.Electronic supplementary materialThe online version of this article (10.1007/s11571-020-09653-y) contains supplementary material, which is available to authorized users.     

Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons

Striatal dopamine plays key roles in our normal and pathological goal-directed actions. To understand dopamine function, much attention has focused on how midbrain dopamine neurons modulate their firing patterns. However, we identify a presynaptic mechanism that triggers dopamine release directly, bypassing activity in dopamine neurons. We paired electrophysiological recordings of striatal channelrhodopsin2-expressing cholinergic interneurons with simultaneous detection of dopamine release at carbon-fiber microelectrodes in striatal slices. We reveal that activation of cholinergic interneurons by light flashes that cause only single action potentials in neurons from a small population triggers dopamine release via activation of nicotinic receptors on dopamine axons. This event overrides ascending activity from dopamine neurons and, furthermore, is reproduced by activating ChR2-expressing thalamostriatal inputs, which synchronize cholinergic interneurons in vivo. These findings indicate that synchronized activity in cholinergic interneurons directly generates striatal dopamine signals whose functions will extend beyond those encoded by dopamine neuron activity.