The pedunculopontine nucleus (PPN) has long been considered an interface between the basal ganglia and motor systems, and its ability to regulate arousal states puts the PPN in a key position to ...modulate behavior. Despite the large amount of data obtained over recent decades, a unified theory of its function is still incomplete. By putting together classical concepts and new evidence that dissects the influence of its different neuronal subtypes on their various targets, we propose that the PPN and, in particular, cholinergic neurons have a central role in updating the behavioral state as a result of changes in environmental contingencies. Such a function is accomplished by a combined mechanism that simultaneously restrains ongoing obsolete actions while it facilitates new contextual associations.
The review by Mena-Segovia and Bolam addresses fundamental aspects of the cellular and functional complexities of the pedunculopontine nucleus. By bringing together classic concepts with emerging new findings, the authors propose a key role in behavioral adaptation during changing contingencies.
Cholinergic transmission in the striatal complex is critical for the modulation of the activity of local microcircuits and dopamine release. Release of acetylcholine has been considered to originate ...exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre(+) transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.
Highlights • The striatum acts as a ‘hub’ that receives afferent inputs from multiple pathways. • Recent studies have characterized several new types of striatal interneurons. • Intrastriatal ...connectivity between interneurons is selective and target-dependent. • New GABAergic, cholinergic, and dopaminergic afferents have been discovered and characterized.
Different striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) ...of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.
► Identified key elements of fundamentally-important dichotomous organization of GPe ► First correlation of GPe neuron firing in vivo with neurochemistry and structure ► Discovered arkypallidal neurons that massively and specifically innervate striatum ► Defined new factors for widespread and excessive beta oscillations in Parkinson's disease
By rigorously defining the neurochemical and structural properties of individual neurons recorded in vivo, Mallet et al. reveal the foundations of a striking functional dichotomy in the external globus pallidus, including a novel cell type that exclusively targets striatum.
Highlights • The dopamine neurons that die in Parkinson's disease are anatomically complex. • Cell trafficking is impaired by the key pathogenic protein in Parkinson's, α-synuclein. • Anatomical ...complexity means that dopamine neurons are susceptible to trafficking deficits. • Familial Parkinson's genes are involved in intracellular trafficking.
Information processing in the striatum is critical for basal ganglia function and strongly influenced by neuromodulators (e.g., dopamine). The striatum also receives modulatory afferents from the ...histaminergic neurons in the hypothalamus which exhibit a distinct diurnal rhythm with high activity during wakefulness, and little or no activity during sleep. In view of the fact that the striatum also expresses a high density of histamine receptors, we hypothesized that released histamine will affect striatal function. We studied the role of histamine on striatal microcircuit function by performing whole-cell patch-clamp recordings of neurochemically identified striatal neurons combined with electrical and optogenetic stimulation of striatal afferents in mouse brain slices. Bath applied histamine had many effects on striatal microcircuits. Histamine, acting at H(2) receptors, depolarized both the direct and indirect pathway medium spiny projection neurons (MSNs). Excitatory, glutamatergic input to both classes of MSNs from both the cortex and thalamus was negatively modulated by histamine acting at presynaptic H(3) receptors. The dynamics of thalamostriatal, but not corticostriatal, synapses were modulated by histamine leading to a facilitation of thalamic input. Furthermore, local inhibitory input to both classes of MSNs was negatively modulated by histamine. Subsequent dual whole-cell patch-clamp recordings of connected pairs of striatal neurons revealed that only lateral inhibition between MSNs is negatively modulated, whereas feedforward inhibition from fast-spiking GABAergic interneurons onto MSNs is unaffected by histamine. These findings suggest that the diurnal rhythm of histamine release entrains striatal function which, during wakefulness, is dominated by feedforward inhibition and a suppression of excitatory drive.
In the subthalamic nucleus (STN) of Parkinson's disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15-30 Hz) accompanies movement difficulties. Abnormal ...beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D(1)/D(2) receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise.
The striatum receives major excitatory inputs from the cortex and thalamus that predominantly target the spines of medium-sized spiny neurons (MSNs). We aimed to determine whether there is any ...selectivity of these two excitatory afferents in their innervation of direct and indirect pathway MSNs. To address this, we used bacterial artificial chromosome transgenic mice, in which enhanced green fluorescent protein (EGFP) reports the presence of D(1) or D(2) dopamine receptor subtypes, markers of direct and indirect pathway MSNs, respectively. Excitatory afferents were identified by the selective expression of vesicular glutamate transporter type 1 (VGluT1) by corticostriatal afferents and vesicular glutamate transporter type 2 (VGluT2) by thalamostriatal afferents. A quantitative electron microscopic analysis was performed on striatal tissue from D(1) and D(2) mice that was double immunolabeled to reveal the EGFP and VGluT1 or VGluT2. We found that the proportion of synapses formed by terminals derived from the cortex and thalamus was similar for both direct and indirect pathway MSNs. Furthermore, qualitative analysis revealed that individual cortical or thalamic terminals form synapses with both direct and indirect pathway MSNs. Similarly, we observed a convergence of cortical and thalamic inputs onto individual MSNs of both direct and indirect pathway: individual EGFP-positive structures received input from both VGluT2-positive and VGluT2-negative terminals. These findings demonstrate that direct and indirect pathway MSNs are similarly innervated by cortical and thalamic afferents; both projections are thus likely to be critical in the control of MSNs and hence play fundamental roles in the expression of basal ganglia function.
The major afferent innervation of the basal ganglia is derived from the cortex and the thalamus. These excitatory inputs mainly target the striatum where they innervate the principal type of striatal ...neuron, the medium-sized spiny neurons (MSNs), and are critical in the expression of basal ganglia function. The aim of this work was to test directly whether corticostriatal and thalamostriatal terminals make convergent synaptic contact with individual direct and indirect pathway MSNs. Individual MSNs were recorded in vivo and labelled by the juxtacellular method in the striatum of BAC transgenic mice in which green fluorescent protein reports the expression of dopamine D1 or D2 receptors. After recovery of the neurons, the tissue was immunolabelled for vesicular glutamate transporters type 1 and 2, as markers of cortical and thalamic terminals, respectively. Three of each class of MSNs were reconstructed in 3D and second-order dendrites selected for electron microscopic analysis. Our findings show that direct and indirect pathway MSNs, located in the matrix compartment of the striatum, receive convergent input from cortex and thalamus preferentially on their spines. There were no differences in the pattern of innervation of direct and indirect pathway MSNs, but the cortical input is more prominent in both and synaptic density is greater for direct pathway neurons. The 3D reconstructions revealed no morphological differences between direct and indirect MSNs. Overall, our findings demonstrate that direct and indirect pathway MSNs located in the matrix receive convergent cortical and thalamic input and suggest that both cortical and thalamic inputs are involved in the activation of MSNs.
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