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.     

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.     

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.     

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.     

Neural mechanisms in disorders of movement

1. Experimental models of ballism, chorea and Parkinson's disease have been developed in the primate, and the underlying neural mechanisms which mediate these disorders of movement have been investigated using the 2-deoxyglucose uptake technique. 2. In ballism, the subthalamic nucleus is either lesioned or underactive. Because of the excitatory nature of subthalamic efferent fibres, this leads to abnormal underactivity of neurons in the medical segment of the globus pallidus which project to the ventral anterior and ventral lateral nuclei of the thalamus, and to the pedunculopontine nucleus of the caudal midbrain. 3. In chorea, there is underactivity of GABAergic striatal (putaminal) neurons which project to the lateral segment of the globus pallidus. This leads to overacting of lateral pallidal neurons and, thus, physiological inhibition of the subthalamic nucleus. Common neural mechanisms, therefore, underlie the appearance of dyskinesia in ballism and chorea. 4. In parkinsonism, there is overactivity of putaminal neurons projecting to the lateral pallidal segment. This results in excessive inhibition of lateral pallidal neurons and, as a consequence, disinhibition of the subthalamic nucleus. Overactivity of the subthalamic nucleus provides excessive drive upon medial pallidal neurons projecting to thalamic and pedunculopontine nuclei.     

A role of dopamine-dependent activity reorganizations in the cortico-basal ganglia-thalamocortical loops in visual attention (hypothetical mechanism)

A mechanism of attention is proposed according to which its influence on visual processing is switched on by release of dopamine into the striatum. A dopamine release during involuntary attention is promoted by visual activation of striatonigral cells via the thalamus and subsequent disinhibition through the basal ganglia of the superior colliculus. A dopamine release during voluntary attention is promoted by activation of prefrontal cortex. The strengthening of responses of neocortical neurons to attended stimulus, and suppression of responses to other stimuli is the result of opposite modulatory action of dopamine on the efficacy of strong and weak corticostriatal inputs. This leads to changes in the output basal ganglia signals ("attentional filter") that exert disinhibitory and inhibitory influence (via the thalamus) on neocortical cells that initially were strongly and weakly activated by a stimulus, respectively. From proposed mechanism follows, that attention modulates only those components of responses of cortical neurons which latency exceeds the latency of reactions of dopaminergic cells (80-100 ms).     

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.     

Mechanisms of effects of adenosine and dopamine on modification of synapses in striato-nigral and striato-pallidal neurons

On the basis of earlier suggested unitary mechanism of synaptic plasticity opposite effects of adenosine and dopamine on the cAMP concentration in striatal spinal cells can emphasize the well known antagonistic interactions between A2A and D2 receptors on striatopallidal cells and between A1 and D1 receptors on striatonigral cells. This is due to that both the dopamine agonist and adenosine antagonist must promote the induction of long-term potentiation/depression of efficacy of excitatory cortical inputs to striatopallidal/striatonigral cells. This modification must lead to synergistic disinhibition of thalamic cells via "direct" and "indirect" pathways through basal ganglia and subsequent strengthening of motor activity.     

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.     

Brain oscillations,medium spiny neurons,and dopamine

1. The striatum is part of a multisynaptic loop involved in translating higher order cognitive activity into action. The main striatal computational unit is the medium spiny neuron, which integrates inputs arriving from widely distributed cortical neurons and provides the sole striatal output.2. The membrane potential of medium spiny neurons' displays shifts between a very negative resting state (down state) and depolarizing plateaus (up states) which are driven by the excitatory cortical inputs.3. Because striatal spiny neurons fire action potentials only during the up state, these plateau depolarizations are perceived as enabling events that allow information processing through cerebral cortex – basal ganglia circuits. In vivo intracellular recording techniques allow to investigate simultaneously the subthreshold behavior of the medium spiny neuron membrane potential (which is a reading of distributed patterns of cortical activity) and medium spiny neuron firing (which is an index of striatal output).4. Recent studies combining intracellular recordings of striatal neurons with field potential recordings of the cerebral cortex illustrate how the analysis of the input–output transformations performed by medium spiny neurons may help to unveil some aspects of information processing in cerebral cortex – basal ganglia circuits, and to understand the origin of the clinical manifestations of Parkinson's disease and other neurologic and neuropsychiatric disorders that result from alterations in dopamine-dependent information processing in the cerebral cortex – basal ganglia circuits.     

Cholinergic and catecholaminergic neurons relay striatal information to the optic tectum in amphibians.

In the amphibians Rana perezi and Xenopus laevis, the involvement of cholinergic and catecholaminergic neurons in the relay of basal ganglia inputs to the tectum was investigated. Tract-tracing experiments, in which anterograde tracers were applied to the basal ganglia and retrograde tracers to the optic tectum, were combined with immunohistochemistry for choline acetyltransferase and tyrosine hydroxylase. The results of these experiments suggest that dopaminergic neurons of the suprachiasmatic nucleus and pretectal region, noradrenergic cells of the locus coeruleus and the cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei mediate at least part of the basal ganglia input to the tectum in anurans.     

Organization of the thalamic and cortical projections of the cat neostriatum]

The investigation has demonstrated that in the cat the nucleus caudatus and the putamen are projected on the cortex and thalamic nuclei of the ipsilateral hemisphere according to a certain topical principle characterized by both similarity in localization of projections of these two structures of the neostriatum and their difference. On the one hand, to the same fields of the cortex and the thalamic nuclei fibres from both structures of the neostriatum go, and on the other hand--a number of cortical zones and thalamic nuclei get projections either from the nucleus caudatus or from the putamen only. Owing to a certain organization of the connections studied, it is possible to consider them as the base of functional heterogeneity of the basal ganglia. Over-lapping of the cortical and thalamic projections of the nucleus caudatus and the putamen might explain common striatal effects on behavioral reactions.     

Cellular principles underlying normal and pathological activity in the subthalamic nucleus

The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system.     

Physiological properties of neurons in superficial layers of superior colliculus of rabbits

Neurons in superficial layers of the superior colliculus of the rabbit are classified into three types by their electrophysiological properties. Among them, two types belong to projecting neurons which send axons to the thalamic pulvinar (N=52) and dorsal lateral geniculate nucleus (N = 54) respectively. All other neurons are pooled into the third type (N=99). Projecting neurons of both types receive monosynaptic visual inputs via optic tract fibers of similar conduction velocity, indicating that in the superior colliculus of the rabbit, there is no difference in conduction velocity between the two pathways. They also receive trisynaptic inhibitory inputs, most likely via recurrent inhibitory circuits. The third type of neurons receives disynaptic optic and trisynaptic inhibitory inputs. The function of neurons of the third type is studied.     

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.     

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.     

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.     

Existence and Control of Go/No-Go Decision Transition Threshold in the Striatum

A typical Go/No-Go decision is suggested to be implemented in the brain via the activation of the direct or indirect pathway in the basal ganglia. Medium spiny neurons (MSNs) in the striatum, receiving input from cortex and projecting to the direct and indirect pathways express D1 and D2 type dopamine receptors, respectively. Recently, it has become clear that the two types of MSNs markedly differ in their mutual and recurrent connectivities as well as feedforward inhibition from FSIs. Therefore, to understand striatal function in action selection, it is of key importance to identify the role of the distinct connectivities within and between the two types of MSNs on the balance of their activity. Here, we used both a reduced firing rate model and numerical simulations of a spiking network model of the striatum to analyze the dynamic balance of spiking activities in D1 and D2 MSNs. We show that the asymmetric connectivity of the two types of MSNs renders the striatum into a threshold device, indicating the state of cortical input rates and correlations by the relative activity rates of D1 and D2 MSNs. Next, we describe how this striatal threshold can be effectively modulated by the activity of fast spiking interneurons, by the dopamine level, and by the activity of the GPe via pallidostriatal backprojections. We show that multiple mechanisms exist in the basal ganglia for biasing striatal output in favour of either the `Go'' or the `No-Go'' pathway. This new understanding of striatal network dynamics provides novel insights into the putative role of the striatum in various behavioral deficits in patients with Parkinson''s disease, including increased reaction times, L-Dopa-induced dyskinesia, and deep brain stimulation-induced impulsivity.     

M₅ muscarinic receptors mediate striatal dopamine activation by ventral tegmental morphine and pedunculopontine stimulation in mice

Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects. M₅ muscarinic receptors are the only muscarinic receptor subtype associated with VTA and SN dopamine neurons. Here we tested the contribution of M₅ muscarinic receptors to morphine-induced dopamine elevations by measuring nucleus accumbens dopamine efflux in response to intra-VTA morphine infusion using in vivo chronoamperometry. Intra-VTA morphine increased nucleus accumbens dopamine efflux in urethane-anesthetized wildtype mice starting at 10 min after infusion. These increases were absent in M₅ knockout mice and were similarly blocked by pre-treatment with VTA scopolamine in wildtype mice. Furthermore, in wildtype mice electrical stimulation of the PPT evoked an initial, short-lasting increase in striatal dopamine efflux, followed 5 min later by a second prolonged increase in dopamine efflux. In M₅ knockout mice, or following systemic pre-treatment with scopolamine in wildtype mice, the prolonged increase in striatal dopamine efflux was absent. The time course of increased accumbal dopamine efflux in wildtype mice following VTA morphine was consistent with both the prolonged M₅-mediated excitation of striatal dopamine efflux following PPT electrical stimulation and accumbal dopamine efflux following LDT electrical stimulation. Therefore, M₅ receptors appear critical for prolonged PPT excitation of dopamine efflux and for dopamine efflux induced by intra-VTA morphine.