Pedunculopontine arousal system physiology - Implications for schizophrenia

Schizophrenia is characterized by major sleep/wake disturbances including increased vigilance and arousal, decreased slow wave sleep, and increased REM sleep drive. Other arousal-related symptoms include sensory gating deficits as exemplified by decreased habituation of the blink reflex. There is also dysregulation of gamma band activity, suggestive of disturbances in a host of arousal-related mechanisms. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of the disease. Recent discoveries on the physiology of the pedunculopontine nucleus help explain many of these disorders of arousal in, and point to novel therapeutic avenues for, schizophrenia.Fil: Garcia Rill, Edgar. University Of Arkansas For Medical Sciences; Estados UnidosFil: D'Onofrio, Stasia. University Of Arkansas For Medical Sciences; Estados UnidosFil: Mahaffey, Susan. University Of Arkansas For Medical Sciences; Estados UnidosFil: Bisagno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Pedunculopontine arousal system physiology– deep brain stimulation (DBS)

This review describes the wake/sleep symptoms present in Parkinson׳s disease, and the role of the pedunculopontine nucleus in these symptoms. The physiology of PPN cells is important not only because it is a major element of the reticular activating system, but also because it is a novel target for deep brain stimulation in the treatment of gait and postural deficits in Parkinson׳s disease. A greater understanding of the physiology of the target nuclei within the brainstem and basal ganglia, amassed over the past decades, has enabled increasingly better patient outcomes from deep brain stimulation for movement disorders.Fil: Garcia Rill, Edgar. University Of Arkansas For Medical Sciences; Estados UnidosFil: Luster, Brennon. University Of Arkansas For Medical Sciences; Estados UnidosFil: D'Onofrio, Stasia. University Of Arkansas For Medical Sciences; Estados UnidosFil: Mahaffey, Susan. University Of Arkansas For Medical Sciences; Estados UnidosFil: Bisagno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires; ArgentinaFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina. Universidad de Buenos Aires; Argentin

Pedunculopontine arousal system physiology—Effects of psychostimulant abuse

This review describes the interactions between the pedunculopontine nucleus (PPN), the ventral tegmental area (VTA), and the thalamocortical system. Experiments using modulators of cholinergic receptors in the PPN clarified its role on psychostimulant-induced locomotion. PPN activation was found to be involved in the animal?s voluntary search for psychostimulants. Every PPN neuron is known to generate gamma band oscillations. Voltage-gated calcium channels are key elements in the generation and maintenance of gamma band activity of PPN neurons. Calcium channels are also key elements mediating psychostimulant-induced alterations in the thalamic targets of PPN output. Thus, the PPN is a key substrate for maintaining arousal and REM sleep, but also in modulating psychostimulant self-administrationFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Bisagno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Gonzalez, Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Rivero Echeto, Maria Celeste Solange. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Muñiz, Javier A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Luster, Brennon. University Of Arkansas For Medical Sciences; Estados UnidosFil: D'onofrio, Stasia. University Of Arkansas For Medical Sciences; Estados UnidosFil: Mahaffey, Susan. University Of Arkansas For Medical Sciences; Estados UnidosFil: Garcia Rill, E. University Of Arkansas For Medical Sciences; Estados Unido

Lithium decreases the effects of neuronal calcium sensor protein 1 on pedunculopontine neurons

Human postmortem studies reported increased expression of neuronal calcium sensor protein 1 (NCS-1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients and was proposed to act by inhibiting the interaction between NCS-1 and inositol 1,4,5-triphosphate receptor protein (InsP3R). NCS-1 is known to enhance the activity of InsP3R, and of Ca2+-mediated gamma oscillatory activity in the pedunculopontine nucleus (PPN), part of the RAS. This study aimed to determine the nature of some of the intracellular mechanisms of Li+ on rat PPN cells and to identify the interaction between Li+ and NCS-1. Since Li+ has been shown to act by inhibiting the enhancing effects of NCS-1, we tested the hypothesis that Li+ would reduce the effects of overexpression of NCS-1 and prevent the downregulation of gamma band activity. Li+ decreased gamma oscillation frequency and amplitude by downregulating Ca2+ channel activity, whereas NCS-1 reduced the effect of Li+ on Ca2+ currents. These effects were mediated by a G-protein overinhibition of Ca2+ currents. These results suggest that Li+ affected intracellular pathways involving the activation of voltage gated Ca2+ channels mediated by an intracellular mechanism involving voltage-dependent activation of G proteins, thereby normalizing gamma band oscillations mediated by P/Q-type calcium channels modulated by NCS-1.Fil: D'Onofrio, Stasia. University of Arkansas for Medical Sciences; Estados UnidosFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Messias, Erick. University of Arkansas for Medical Sciences; Estados UnidosFil: Garcia Rill, Edgar. University of Arkansas for Medical Sciences; Estados Unido

Lithium decreases the effects of neuronal calcium sensor protein 1 on pedunculopontine neurons

Human postmortem studies reported increased expression of neuronal calcium sensor protein 1 (NCS-1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients and was proposed to act by inhibiting the interaction between NCS-1 and inositol 1,4,5-triphosphate receptor protein (InsP3R). NCS-1 is known to enhance the activity of InsP3R, and of Ca2+-mediated gamma oscillatory activity in the pedunculopontine nucleus (PPN), part of the RAS. This study aimed to determine the nature of some of the intracellular mechanisms of Li+ on rat PPN cells and to identify the interaction between Li+ and NCS-1. Since Li+ has been shown to act by inhibiting the enhancing effects of NCS-1, we tested the hypothesis that Li+ would reduce the effects of overexpression of NCS-1 and prevent the downregulation of gamma band activity. Li+ decreased gamma oscillation frequency and amplitude by downregulating Ca2+ channel activity, whereas NCS-1 reduced the effect of Li+ on Ca2+ currents. These effects were mediated by a G-protein overinhibition of Ca2+ currents. These results suggest that Li+ affected intracellular pathways involving the activation of voltage gated Ca2+ channels mediated by an intracellular mechanism involving voltage-dependent activation of G proteins, thereby normalizing gamma band oscillations mediated by P/Q-type calcium channels modulated by NCS-1.Fil: D'Onofrio, Stasia. University of Arkansas for Medical Sciences; Estados UnidosFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Messias, Erick. University of Arkansas for Medical Sciences; Estados UnidosFil: Garcia Rill, Edgar. University of Arkansas for Medical Sciences; Estados Unido

High-Threshold Ca2+ channels behind gamma band activity in the pedunculopontine nucleus (PPN)

The pedunculopontine nucleus (PPN) is part of the Reticular Activating System, and active during waking and REM sleep. Previous results showed that all PPN cells plateau at gamma frequencies and intrinsic membrane oscillations in PPN neuons are mediated by high threshold N- and P/Q-type Ca2+ channels. The present study was designed to determine whether some PPN cells have only N-, only P/Q-, or both N- and P/Q-type Ca2+ channels. We used patch clamp recordings in PPN cells in slices from anesthetized rat pups in the presence of synaptic receptor blockers (SB) and Tetrodotoxin (TTX), and applied ramps to induce intrinsic membrane oscillations. We found that all PPN cell types showed gamma oscillations in the presence of SB+TTX when using current ramps. In 50% of cells, the N-type Ca2+ channel blocker ω-Conotoxin-GVIA (ω-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker ω- Agatoxin-IVA (ω-Aga) blocked the remaining oscillations. Another 20% manifested gamma oscillations that were not significantly affected by the addition of ω-CgTx, however, ω-Aga blocked the remaining oscillations. In 30% of cells, ω-Aga had no effect on gamma oscillations, while ω-CgTx blocked them. These novel results confirm the segregation of populations of PPN cells as a function of the calcium channels expressed, i.e. the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, and both N-type and P/Q-type Ca2+ channels.Fil: Luster, Brennon. Center For Translational Neuroscience; Estados UnidosFil: D'Onofrio, Stasia. Center For Translational Neuroscience; Estados UnidosFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Garcia Rill, Edgar. Center For Translational Neuroscience; Estados Unido

Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: Relevance to schizophrenia and bipolar disorder

Reduced levels of gamma-band activity are present in schizophrenia and bipolar disorder patients. In the same disorders, increased neuronal calcium sensor protein-1 (NCS-1) expression was reported in a series of postmortem studies. These disorders are also characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). The discovery of gamma-band activity in the pedunculopontine nucleus (PPN), the cholinergic arm of the RAS, revealed that such activity was mediated by high-threshold calcium channels that are regulated by NCS-1.We hypothesized that NCS-1 normally regulates gamma-band oscillations through these calcium channels and that excessive levels of NCS-1, such as would be expected with overexpression, decrease gammaband activity. We found that PPN neurons in rat brain slices manifested gamma-band oscillations that were increased by low levels of NCS-1 but suppressed by high levels of NCS-1.Our results suggest that NCS-1 overexpression may be responsible for the decrease in gamma-band activity present in at least some schizophrenia and bipolar disorder patients.Fil: D'Onofrio, Stasia. University Of Arkansas For Medical Sciences; Estados UnidosFil: Kezunovic, Nebojsa. University Of Arkansas For Medical Sciences; Estados UnidosFil: Hyde, James. University Of Arkansas For Medical Sciences; Estados UnidosFil: Luster, Brennon. University Of Arkansas For Medical Sciences; Estados UnidosFil: Messias, Erick. University Of Arkansas For Medical Sciences; Estados UnidosFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Garcia Rill, Edgar. University Of Arkansas For Medical Sciences; Estados Unido