Changes in neuronal activity of cortico‐basal ganglia–thalamic networks induced by acute dopaminergic manipulations in rats

The basal ganglia are thought to be particularly sensitive to changes in dopaminergic tone, and the realization that reduced dopaminergic signaling causes pronounced motor dysfunction is the rationale behind dopamine replacement therapy in Parkinson's disease. It has, however, proven difficult to identify which neurophysiological changes that ultimately lead to motor dysfunctions. To clarify this, we have here recorded neuronal activity throughout the cortico‐basal ganglia–thalamic circuits in freely behaving rats during periods of immobility following acute dopaminergic manipulations, involving both vesicular dopamine depletion and antagonism of D1 and D2 type dopamine receptors. Synchronized and rhythmic activities were detected in the form of betaband oscillations in local field potentials and as cortical entrainment of action potentials in several basal ganglia structures. Analyses of the temporal development of synchronized oscillations revealed a spread from cortex to gradually also include deeper structures. In addition, firing rate changes involving neurons in all parts of the network were observed. These changes were typically relatively balanced within each structure, resulting in negligible net rate changes. Animals treated with D1 receptor antagonist showed a rapid onset of hypokinesia that preceded most of the neurophysiological changes, with the exception of these balanced rate changes. Parallel rate changes in functionally coupled ensembles of neurons in different structures may therefore be the first step in a cascade of neurophysiological changes underlying motor symptoms in the parkinsonian state. We suggest that balanced rate changes in distributed networks are possible mechanism of disease that should be further investigated in conditions involving dopaminergic dysfunction.     

Parafascicular thalamic nucleus activity in a rat model of Parkinson's disease

Parkinson's disease is associated with increased oscillatory firing patterns in basal ganglia output, which are thought to disrupt thalamocortical activity. However, it is unclear how specific thalamic nuclei are affected by these changes in basal ganglia activity. The thalamic parafascicular nucleus (PFN) receives input from basal ganglia output nuclei and directly projects to the subthalamic nucleus (STN), striatum and cortex; thus basal ganglia-mediated changes on PFN activity may further impact basal ganglia and cortical functions. To investigate the impact of increased oscillatory activity in basal ganglia output on PFN activity after dopamine cell lesion, PFN single-unit and local field potential activities were recorded in neurologically intact (control) rats and in both non-lesioned and dopamine lesioned hemispheres of unilateral 6-hydroxydopamine lesioned rats anesthetized with urethane. Firing rates were unchanged 1–2 weeks after lesion; however, significantly fewer spontaneously active PFN neurons were evident. Firing pattern assessments after lesion showed that a larger proportion of PFN spike trains had 0.3–2.5 Hz oscillatory activity and significantly fewer spike trains exhibited low threshold calcium spike (LTS) bursts. In paired recordings, more PFN–STN spike oscillations were significantly correlated, but as these oscillations were in-phase, results are inconsistent with feedforward control of PFN activity by inhibitory oscillatory basal ganglia output. Furthermore, the decreased incidence of LTS bursts is incompatible with inhibitory basal ganglia output inducing rebound bursting in PFN after dopamine lesion. Together, results show that robust oscillatory activity observed in basal ganglia output nuclei after dopamine cell lesion does not directly drive changes in PFN oscillatory activity.     

Striatal dysfunction increases basal ganglia output during motor cortex activation in parkinsonian rats

During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.     

State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats

Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, 7 d after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8-25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25-40 Hz band with a peak frequency at 30-35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons, and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25-40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity.     

The spontaneous firing patterns of forebrain neurons. IV. Effects of bilateral and unilateral frontal cortical ablations on firing of caudate, globus pallidus and thalamic neurons

To assess the effects of partial deafferentation of the neostriatum on spontaneous neuronal activity in the basal ganglia and related thalamic nuclei, ablations of frontal cortex were carried out in adult cats. Postoperative measures of interspike intervals of single neurons in the caudate nucleus, globus pallidus and ventral anterior-ventral lateral complex of the thalamus revealed a slowing of neuronal firing in these structures as compared with non-lesioned controls. The fact that deafferentation by cortical damage produces changes in neuronal firing in target neurons of the striatum (globus pallidus) and in thalamic neurons at least two synapses removed from the striatum is noteworthy. The possible extent to which these results might have been influenced by reduction of cortical inputs to or denervation of the thalamus is discussed.     

Facing the lack of anti-phase oscillation in the parafascicular nucleus after dopamine depletion

There is a large body of literature establishing that excessive neuronal synchronization and a shift in firing pattern within the cortico-basal ganglia circuit is implicated in Parkinson's disease (PD), yet a causal link between abnormal network oscillation and specific deficits in PD is lacking. It is proposed that enhanced (inhibitory) synchronous basal ganglia output could trigger anti-phase oscillatory activity in target thalamic nuclei, and entrain this abnormal synchronization within the cortico-basal ganglia loop through a reciprocal resonance mechanism. In a recent Experimental Neurology paper (2009), Parr-Brownlie et al. addressed this issue by assessing electrophysiological recordings in vivo in anesthetized control and dopamine-depleted rats induced by unilateral injection of 6-hydroxydopamine. Results from this study demonstrate that a shift in firing pattern in basal ganglia output neurons does not directly drive the distinctive oscillatory activity observed in the parafascicular nucleus after dopamine depletion. This commentary discusses possible mechanisms mediating the altered oscillatory activity found in the parafascicular nucleus after dopamine depletion and its link to the increased in-phase oscillations with synchronous firing in the subthalamic nucleus.     

Tremor-related activity of neurons in the 'motor' thalamus: changes in firing rate and pattern in the MPTP vervet model of parkinsonism

The pathophysiology of parkinsonian tremor remains a matter of debate with two opposing hypotheses proposing a peripheral and a central origin, respectively. A central origin of tremor could arise either from a rhythmic activity of the internal segment of the globus pallidus (GPi) or from a structure such as the thalamus, outside the basal ganglia. In this study, single-unit recordings were performed in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys within the GPi and within three territories of the motor thalamus (delimited by their afferent inputs from the GPi, the substantia nigra and the cerebellum, respectively). For each recorded neuron, we compared the variations in firing rate and pattern in tremor and no tremor periods. Tremor either occurred spontaneously or was induced by external stimulation. When the animals entered into a tremor period we observed: (i) an increase in the mean firing rate in about half of the recorded neurons of the motor thalamus; and (ii), a change from an irregular to a rhythmic discharge within the range of tremor frequency (5-7 Hz) in about 10% of the recorded neurons of the motor thalamus (pallidal and cerebellar territories) and the GPi. Most of the thalamic neurons that exhibited a rhythmic discharge during tremor were found to be sensitive to external stimulation. Because the changes in firing rate occurred predominantly in the motor thalamus and not in the GPi, and because a fast rhythmic discharge of 10-15 Hz was frequently observed in the GPi and not in the motor thalamus, we conclude that thalamic activity is not a simple reproduction of basal ganglia output. Moreover, we suggest that thalamic processing of basal ganglia outputs could participate in the genesis of tremor, and that this thalamic processing could be influenced by sensory inputs and/or changes in attentional level elicited by external stimulation.     

Pathophysiology of parkinsonism.

The motor signs of Parkinson's disease are thought to result in large part from a reduction of the level of dopamine in the basal ganglia. Over the last few years, many of the functional and anatomical consequences of dopamine loss in these structures have been identified, both in the basal ganglia and in related areas in thalamus and cortex. This knowledge has contributed significantly to our understanding of the link between the degeneration of dopamine neurons in the midbrain and the development of parkinsonism. This review discusses the evidence that implicates electrophysiologic changes (including altered discharge rates, increased incidence of burst firing, interneuronal synchrony, oscillatory activity, and altered sensorimotor processing) in basal ganglia, thalamus, and cortex, in parkinsonism. From these studies, parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affects the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions. Detailed knowledge of these changes will help us to develop more effective and specific symptomatic treatments for patients with Parkinson's disease.     

Neuronal activity in the monkey motor thalamus during bicuculline-induced dystonia

Recent data suggest that a decreased basal ganglia output may occur in dystonia, resulting in an increased thalamic drive to the mesial premotor cortex. In a previous work we found that injection of the GABAA antagonist bicuculline into the rostral motor thalamus induced contralateral dystonic postures, whereas myoclonic jerks were frequent after injection into the caudal motor thalamus. In the present study, we performed electrophysiological recordings in the rostral and caudal parts of the ventrolateral thalamus of two cynomolgus monkeys before and after bicuculline injections or saline injections. Discharge frequencies of thalamic neurons were increased after bicuculline injections vs. controls. Their discharge pattern was more bursty in the caudal part in which bursts of neuronal activity were correlated with myoclonic jerks. After bicuculline injection, neurons responded more frequently and less selectively to passive limb movements in both parts of the motor thalamus. Conversely, the response to microstimulation increased after bicuculline injection, particularly in the caudal part. Our data show that acute bicuculline-induced dystonia is associated with a reversible overactivity and disorganization of neuronal activity in the motor thalamus. Such a phenomenon might induce an overspreading of cortical activity leading to dystonia. We postulate that the distinct clinical syndromes observed after bicuculline injections into the rostral and caudal motor thalamus are due to differences both in the neuronal circuitry within each thalamic nucleus and in segregated cortical projections.     

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

The pedunculopontine nucleus (PPN) is a new deep brain stimulation (DBS) target for Parkinson's disease (PD), but little is known about PPN firing pattern alterations in PD. The anesthetized rat is a useful model for investigating the effects of dopamine loss on the transmission of oscillatory cortical activity through basal ganglia structures. After dopamine loss, synchronous oscillatory activity emerges in the subthalamic nucleus and substantia nigra pars reticulata in phase with cortical slow oscillations. To investigate the impact of dopamine cell lesion-induced changes in basal ganglia output on activity in the PPN, this study examines PPN spike timing with reference to motor cortex (MCx) local field potential (LFP) activity in urethane- or ketamine-anesthetized rats. Seven to ten days after unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, spectral power in PPN spike trains and coherence between PPN spiking and PPN LFP activity increased in the  1 Hz range in urethane-anesthetized rats. PPN spike timing also changed from firing predominantly in phase with MCx slow oscillations in the intact urethane-anesthetized rat to firing predominantly antiphase to MCx oscillations in the hemi-parkinsonian rat. These changes were not observed in the ketamine-anesthetized preparation. These observations suggest that dopamine loss alters PPN spike timing by increasing inhibitory oscillatory input to the PPN from basal ganglia output nuclei, a phenomenon that may be relevant to motor dysfunction and PPN DBS efficacy in PD patients.     

Sensory-motor disintegration in the basal ganglia disorders]

Basal ganglia lie between the cerebral cortex and the thalamus, and have dense fiber connections between them. These connections form 4-5 distinct loops to allow parallel processing of information. Among them, the most intensively studied is the motor loop, which comprises 2 distinct direct and indirect pathways. The direct pathway disinhibits the powerful inhibition of Gpi/SNr upon the thalamic VL nuclei with a net result of facilitatory influence upon the motor cortex. By contrast, the indirect pathway exerts an inhibitory effect. Overall this dual system provides a center-surround mechanism to focus its effect on selected cortical neurons. The functional role of the loop in motor control has not been precisely understood. Several lines of evidence have recently been presented to support the view that this mechanism is used to focus the output to a specific group of muscles required for performing a specific task. Recent observations in dystonia and Parkinsonism suggest that this operation is made possible through opening the sensory channel for the expected sensory feed-back afferents during movement. Thus one of the important functions of basal ganglia seems to be the gating of sensory input for motor control.     

Parvalbumin‐producing striatal interneurons receive excitatory inputs onto proximal dendrites from the motor thalamus in male mice

In rodents, the dorsolateral striatum regulates voluntary movement by integrating excitatory inputs from the motor‐related cerebral cortex and thalamus to produce contingent inhibitory output to other basal ganglia nuclei. Striatal parvalbumin (PV)‐producing interneurons receiving this excitatory input then inhibit medium spiny neurons (MSNs) and modify their outputs. To understand basal ganglia function in motor control, it is important to reveal the precise synaptic organization of motor‐related cortical and thalamic inputs to striatal PV interneurons. To examine which domains of the PV neurons receive these excitatory inputs, we used male bacterial artificial chromosome transgenic mice expressing somatodendritic membrane–targeted green fluorescent protein in PV neurons. An anterograde tracing study with the adeno‐associated virus vector combined with immunodetection of pre‐ and postsynaptic markers visualized the distribution of the excitatory appositions on PV dendrites. Statistical analysis revealed that the density of thalamostriatal appositions along the dendrites was significantly higher on the proximal than distal dendrites. In contrast, there was no positional preference in the density of appositions from axons of the dorsofrontal cortex. Population observations of thalamostriatal and corticostriatal appositions by immunohistochemistry for pathway‐specific vesicular glutamate transporters confirmed that thalamic inputs preferentially, and cortical ones less preferentially, made apposition on proximal dendrites of PV neurons. This axodendritic organization suggests that PV neurons produce fast and reliable inhibition of MSNs in response to thalamic inputs and process excitatory inputs from motor cortices locally and plastically, possibly together with other GABAergic and dopaminergic dendritic inputs, to modulate MSN inhibition.     

Thalamic afferents to prefrontal cortices from ventral motor nuclei in decision‐making

The focus of this literature review is on the three interacting brain areas that participate in decision‐making: basal ganglia, ventral motor thalamic nuclei, and medial prefrontal cortex, with an emphasis on the participation of the ventromedial and ventral anterior motor thalamic nuclei in prefrontal cortical function. Apart from a defining input from the mediodorsal thalamus, the prefrontal cortex receives inputs from ventral motor thalamic nuclei that combine to mediate typical prefrontal functions such as associative learning, action selection, and decision‐making. Motor, somatosensory and medial prefrontal cortices are mainly contacted in layer 1 by the ventral motor thalamic nuclei and in layer 3 by thalamocortical input from mediodorsal thalamus. We will review anatomical, electrophysiological, and behavioral evidence for the proposed participation of ventral motor thalamic nuclei and medial prefrontal cortex in rat and mouse motor decision‐making.     

Thalamic noradrenaline in Parkinson's disease: Deficits suggest role in motor and non‐motor symptoms

The thalamus occupies a pivotal position within the corticobasal ganglia‐cortical circuits. In Parkinson's disease (PD), the thalamus exhibits pathological neuronal discharge patterns, foremost increased bursting and oscillatory activity, which are thought to perturb the faithful transfer of basal ganglia impulse flow to the cortex. Analogous abnormal thalamic discharge patterns develop in animals with experimentally reduced thalamic noradrenaline; conversely, added to thalamic neuronal preparations, noradrenaline exhibits marked antioscillatory and antibursting activity. Our study is based on this experimentally established link between noradrenaline and the quality of thalamic neuronal discharges. We analyzed 14 thalamic nuclei from all functionally relevant territories of 9 patients with PD and 8 controls, and measured noradrenaline with high‐performance liquid chromatography with electrochemical detection. In PD, noradrenaline was profoundly reduced in all nuclei of the motor (pallidonigral and cerebellar) thalamus (ventroanterior: ?86%, P = .0011; ventrolateral oral: ?87%, P = .0010; ventrolateral caudal: ?89%, P = .0014): Also, marked noradrenaline losses, ranging from 68% to 91% of controls, were found in other thalamic territories, including associative, limbic and intralaminar regions; the primary sensory regions were only mildly affected. The marked noradrenergic deafferentiation of the thalamus discloses a strategically located noradrenergic component in the overall pathophysiology of PD, suggesting a role in the complex mechanisms involved with the genesis of the motor and non‐motor symptoms. Our study thus significantly contributes to the knowledge of the extrastriatal nondopaminergic mechanisms of PD with direct relevance to treatment of this disorder. © 2012 Movement Disorder Society     

Oscillations in the basal ganglia under normal conditions and in movement disorders.

A substantial body of work within the last decade has demonstrated that there is a variety of oscillatory phenomena that occur in the basal ganglia and in associated regions of the thalamus and cortex. Most of the earlier studies focused on recordings in rodents and primates. More recently, significant advances have been made in this field of research through the analysis of basal ganglia field potentials recorded from implanted deep brain stimulation electrodes in the basal ganglia of human patients with Parkinson's disease and other disorders. It now appears that oscillatory activity may play a significant role in the pathogenesis of these diseases. The most significant finding is that in Parkinson's disease synchronized oscillatory activity in the 10- to 35-Hz band (often termed "beta-band") is prevalent in the basal ganglia-thalamocortical circuits, and that such activity can be reduced by dopaminergic treatments. The entrainment of large portions of these circuits may disrupt information processing in them and may lead to parkinsonian akinesia (and perhaps tremor). Although less firmly established than the role of oscillations in movement disorders, oscillatory activities at higher frequencies may also be a component of normal basal ganglia physiology.     

Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

The hypokinetic motor symptoms of Parkinson''s disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine (DA) alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL/6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer (L)5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials (APs) in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability in parkinsonism was caused by an impaired function of both persistent sodium channels and the large conductance, Ca²⁺-activated K⁺ channels. Acute activation of dopaminergic receptors failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data demonstrated a cell type-specific decrease of the excitability of M1 pyramidal neurons in parkinsonism. Thus, intrinsic adaptations in the motor cortex provide novel insight in our understanding of the pathophysiology of motor deficits in PD.SIGNIFICANCE STATEMENT The degeneration of midbrain dopaminergic neurons in Parkinson''s disease (PD) remodels the connectivity and function of cortico–basal ganglia–thalamocortical network. However, whether and how dopaminergic degeneration and the associated basal ganglia dysfunction alter motor cortical circuitry remain undefined. We found that pyramidal neurons in the layer (L)5b of the primary motor cortex (M1) exhibit distinct adaptations in response to the loss of midbrain dopaminergic neurons, depending on their long-range projections. Besides the decreased thalamocortical synaptic excitation as proposed by the classical model of Parkinson''s pathophysiology, these results, for the first time, show novel cellular and molecular mechanisms underlying the abnormal motor cortical output in parkinsonism.     

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity

BackgroundEpileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations.HypothesisHere we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity.MethodsWe performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings.ResultsWe show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all.ConclusionOur data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.     

Differentiated participation of thalamocortical subnetworks in slow/spindle waves and desynchronization

During sleep, the electroencephalogram exhibits synchronized slow waves that desynchronize when animals awaken [desynchronized states (DSs)]. During slow-wave states, the membrane potentials of cortical neurons oscillate between discrete depolarized states ("Up states") and periods of hyperpolarization ("Down states"). To determine the role of corticothalamic loops in generating Up/Down oscillations in rats, we recorded unit activities of layer 5 (L5) corticothalamic (CTh) cells in the frontal cortex, neurons in the thalamic reticular nucleus, and basal ganglia- and cerebellum-linked thalamic relay nuclei, while simultaneously monitoring the local cortical field potential to identify slow-wave/spindle oscillations and desynchronization. We found that (1) some basal ganglia-linked and reticular thalamic cells fire preferentially near the beginning of Up states; (2) thalamic cells fire more selectively at a given Up-state phase than do CTh cells; (3) CTh and thalamic cells exhibit different action potential timings within spindle cycles; and (4) neurons exhibit different firing characteristics when comparing their activity during Up states and DSs. These data demonstrate that cortico-thalamo-cortical subnetworks are temporally differentiated during slow and spindle oscillations, that the basal ganglia-linked thalamic nuclei are closely related with Up-state initiation, and that Up states and DSs are distinguished as different depolarization states of neurons within the network.     

An outline of brain function

An outline of how the brain may compute is proposed. In the cerebral cortex memories are stored through long-term potentiation at synapses from layer 1 cortical inputs (representing contexts) on layer 2/3 pyramidal cells linked with the thalamus in a cortico-thalamic (CT) unit. The signals which are memorized are the layer 3 inputs from the thalamus or other cortical areas. Signals are memorized (and later recalled) at the gamma frequency. A conscious thought comprises the outputs of layer 5 cells in CT units in different cortical regions firing in synchrony through the contribution of oscillatory thalamic and cortical inputs. This cortical output influences sub-cortical areas to cause or participate in a movement. Cerebral cortical outputs may be stored in the cerebellum and generated later in a particular context by the basal ganglia and cerebellum. Thus the brain may either generate 'conscious' outputs using the cerebral cortex or 'automatic' outputs using the basal ganglia and cerebellum. When contexts are recognized by the basal ganglia it permits outputs stored in the cerebellum to commence and in this way the basal ganglia can control complex sequences of outputs or movements. Working memory involves the prefrontal cortex using similarly the basal ganglia and cerebellum. The hippocampus has a role in the storage and recall of cortical outputs by providing unique layer 1 contexts to all the CT loops in different cortical areas in a conscious thought. With further recall of the thought new layer 1 contexts may become associated with the CT loops enabling recall without the hippocampal input.     

Functional anatomy of thalamus and basal ganglia

THALAMUS: The human thalamus is a nuclear complex located in the diencephalon and comprising of four parts (the hypothalamus, the epythalamus, the ventral thalamus, and the dorsal thalamus). The thalamus is a relay centre subserving both sensory and motor mechanisms. Thalamic nuclei (50-60 nuclei) project to one or a few well-defined cortical areas. Multiple cortical areas receive afferents from a single thalamic nucleus and send back information to different thalamic nuclei. The corticofugal projection provides positive feedback to the "correct" input, while at the same time suppressing irrelevant information. Topographical organisation of the thalamic afferents and efferents is contralateral, and the lateralisation of the thalamic functions affects both sensory and motoric aspects. Symptoms of lesions located in the thalamus are closely related to the function of the areas involved. An infarction or haemorrhage thalamic lesion can develop somatosensory disturbances and/or central pain in the opposite hemibody, analgesic or purely algesic thalamic syndrome characterised by contralateral anaesthesia (or hypaesthesia), contralateral weakness, ataxia and, often, persistent spontaneous pain. BASAL GANGLIA: Basal ganglia form a major centre in the complex extrapyramidal motor system, as opposed to the pyramidal motor system (corticobulbar and corticospinal pathways). Basal ganglia are involved in many neuronal pathways having emotional, motivational, associative and cognitive functions as well. The striatum (caudate nucleus, putamen and nucleus accumbens) receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas (prefrontal, premotor and supplementary motor areas) which are concerned with motor planning. These circuits: (i) have an important regulatory influence on cortex, providing information for both automatic and voluntary motor responses to the pyramidal system; (ii) play a role in predicting future events, reinforcing wanted behaviour and suppressing unwanted behaviour, and (iii) are involved in shifting attentional sets and in both high-order processes of movement initiation and spatial working memory. Basal ganglia-thalamo-cortical circuits maintain somatotopic organisation of movement-related neurons throughout the circuit. These circuits reveal functional subdivisions of the oculomotor, prefrontal and cingulate circuits, which play an important role in attention, learning and potentiating behaviour-guiding rules. Involvement of the basal ganglia is related to involuntary and stereotyped movements or paucity of movements without involvement of voluntary motor functions, as in Parkinson's disease, Wilson's disease, progressive supranuclear palsy or Huntington's disease. The symptoms differ with the location of the lesion. The commonest disturbances in basal ganglia lesions are abulia (apathy with loss of initiative and of spontaneous thought and emotional responses) and dystonia, which become manifest as behavioural and motor disturbances, respectively.