The interest in the pedunculopontine tegmental nucleus (PPTg), a structure located in the brainstem at the level of the pontomesencephalic junction, has greatly increased in recent years because it ...is involved in the regulation of physiological functions that fail in Parkinson's disease and because it is a promising target for deep brain stimulation in movement disorders. The PPTg is highly interconnected with the main basal ganglia nuclei and relays basal ganglia activity to thalamic and brainstem nuclei and to spinal effectors. In this review, we address the functional role of the main PPTg outputs directed to the basal ganglia, thalamus, cerebellum and spinal cord. Together, the data that we discuss show that the PPTg may influence thalamocortical activity and spinal motoneuron excitability through its ascending and descending output fibers, respectively. Cerebellar nuclei may also relay signals from the PPTg to thalamic and brainstem nuclei. In addition to participating in motor functions, the PPTg participates in arousal, attention, action selection and reward mechanisms. Finally, we discuss the possibility that the PPTg may be involved in excitotoxic degeneration of the dopaminergic neurons of the substantia nigra through the glutamatergic monosynaptic input that it provides to these neurons.
•The pedunculopontine tegmental nucleus is not a mere interface between the basal ganglia and spinal cord•It has an active role in sensorimotor control and higher functions of the brain•Its continuous stimulation may improve motor disabilities in Parkinson's Disease•Its neurons may participate in neurodegenerative mechanisms
Abstract
The unconventional normal-state properties of the cuprates are often discussed in terms of emergent electronic order that onsets below a putative critical doping of
x
c
≈ 0.19. Charge ...density wave (CDW) correlations represent one such order; however, experimental evidence for such order generally spans a limited range of doping that falls short of the critical value
x
c
, leading to questions regarding its essential relevance. Here, we use X-ray diffraction to demonstrate that CDW correlations in La
2−
x
Sr
x
CuO
4
persist up to a doping of at least
x
= 0.21. The correlations show strong changes through the superconducting transition, but no obvious discontinuity through
x
c
≈ 0.19, despite changes in Fermi surface topology and electronic transport at this doping. These results demonstrate the interaction between CDWs and superconductivity even in overdoped cuprates and prompt a reconsideration of the role of CDW correlations in the high-temperature cuprate phase diagram.
Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend ...on dopamine signals in the striatum, the way the circuits that mediate goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of spiny projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN transmodulation across the striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.
Coughing in humans is typically preceded by a desire (or urge) to cough. The neural circuitry involved in sensing airway irritation and generating the urge-to-cough in humans is essentially unknown.
...The aim of the present study was to use functional brain imaging to describe the supramedullary regions that are activated in humans during capsaicin inhalation.
Experiments were performed on 10 healthy subjects (5 males, 5 females). Capsaicin doses were individually tailored to evoke a transient and reversible urge-to-cough. Blood oxygen level-dependent (BOLD) functional magnetic resonance measures were collected during repeated 24-second challenges with capsaicin or saline inhalation and subjects were asked to rate the urge-to-cough intensity of each challenge.
Capsaicin inhalation reliably evoked an urge-to-cough, which was associated with activations in a variety of brain regions, including the insula cortex, anterior midcingulate cortex, primary sensory cortex, orbitofrontal cortex, supplementary motor area, and cerebellum.
These data provide the first insights into the cortical neuronal network involved in sensing airway irritation and modulating coughing in humans.
Sensory nerves innervating the mucosa of the airways monitor the local environment for the presence of irritant stimuli and, when activated, provide input to the nucleus of the solitary tract (Sol) ...and paratrigeminal nucleus (Pa5) in the medulla to drive a variety of protective behaviors. Accompanying these behaviors are perceivable sensations that, particularly for stimuli in the proximal end of the airways, can be discrete and localizable. Airway sensations likely reflect the ascending airway sensory circuitry relayed via the Sol and Pa5, which terminates broadly throughout the CNS. However, the relative contribution of the Sol and Pa5 to these ascending pathways is not known. In the present study, we developed and characterized a novel conditional anterograde transneuronal viral tracing system based on the H129 strain of herpes simplex virus 1 and used this system in rats along with conventional neuroanatomical tracing with cholera toxin B to identify subcircuits in the brainstem and forebrain that are in receipt of relayed airway sensory inputs via the Sol and Pa5. We show that both the Pa5 and proximal airways disproportionately receive afferent terminals arising from the jugular (rather than nodose) vagal ganglia and the output of the Pa5 is predominately directed toward the ventrobasal thalamus. We propose the existence of a somatosensory-like pathway from the proximal airways involving jugular ganglia afferents, the Pa5, and the somatosensory thalamus and suggest that this pathway forms the anatomical framework for sensations arising from the proximal airway mucosa.
Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial ...in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2-6 months after surgery in the OFF- and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3-6 months. In contrast, bilateral STN-DBS at 130-185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities. These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive.
Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through ...which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT
) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF
) in mice. Specifically, 5-HT
projections to the BNST, via actions at 5-HT
receptors (5-HT
Rs), engage a CRF
inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF
inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF
R, also known as CRHR1), given that CRF
R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT
→CRF
circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.
•Airway nociceptors are derived from jugular or nodose vagal ganglia.•Jugular and nodose nociceptors differ in embryology, phenotype, function and anatomical wiring.•Jugular nociceptors may play a ...critical role in cough and airway sensation.•Jugular nociceptors and their central signaling may be a new target for relieving chronic cough.
The airways receive a dense supply of sensory nerve fibers that are responsive to damaging or potentially injurious stimuli. These airway nociceptors are mainly derived from the jugular and nodose vagal ganglia, and when activated they induce a range of reflexes and sensations that play an essential role in airway protection. Jugular nociceptors differ from nodose nociceptors in their embryonic origins, molecular profile and termination patterns in the airways and the brain, and recent discoveries suggest that excessive activity in jugular nociceptors may be central to the development of chronic cough. For these reasons, targeting jugular airway nociceptor signaling processes at different levels of the neuraxis may be a promising target for therapeutic development. In this focused review, we present the current understanding of jugular ganglia nociceptors, how they may contribute to chronic cough and mechanisms that could be targeted to bring about cough suppression.
Abstract While excitotoxicity is a major contributor to the pathophysiology of acute spinal injury, its time course and the extent of cell damage in relation to locomotor network activity remain ...unclear. We used two in vitro models, that is, the rat isolated spinal cord and spinal organotypic cultures, to explore the basic characteristics of excitotoxicity caused by transient application of the glutamate analogue kainate followed by washout and analysis 24 h later. Electrophysiological records showed that fictive locomotion was slowed down by 10 μM kainate (with no histological loss) and fully abolished by 50 μM, while disinhibited bursting with unchanged periodicity persisted. Kainate concentrations (≥50 μM) larger than those necessary to irreversible suppress fictive locomotion could still elicit dose-dependent motoneuron pool depolarization, and dose-dependent neuronal loss in the grey matter, especially evident in central and dorsal areas. Motoneuron numbers were largely decreased. A similar regional pattern was detected in organotypic slices, as extensive cell loss was dose related and affected motoneurons and premotoneurons: the number of dead neurons (already apparent 1 h after kainate) grew faster with the higher kainate concentration. The histological damage was accompanied by decreased MTT formazan production commensurate with the number of surviving cells. Our data suggest locomotor network function was very sensitive to excitotoxicity, even without observing extensive cell death. Excitotoxicity developed gradually leaving a time window in which neuroprotection might be attempted to preserve circuits still capable of expressing basic rhythmogenesis and reconfigure their function in terms of locomotor output.
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