Recording Gamma Band Oscillations in Pedunculopontine Nucleus Neurons

Synaptic efferents from the PPN are known to modulate the neuronal activity of several intralaminar thalamic regions (e.g., the ...

University of Arkansas for Medical Sciences

The pedunculopontine nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular nucleus (Pf), and pontine subcoeruleus nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS.

Pedunculopontine Nucleus Gamma Band Activity-Preconscious Awareness, Waking, and REM Sleep.

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 gamma-band 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.

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

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 neurons are mediated by high-threshold N- and P/Q-type Ca(2+) 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 Ca(2+) 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 Ca(2+) 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, that is, 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 Ca(2+) channels.

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

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.

Pedunculopontine arousal system physiology-Implications for schizophrenia.

This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca(2+) channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle.

Pedunculopontine Gamma Band Activity and Development.

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.

Pedunculopontine arousal system physiology - Deep brain stimulation (DBS).

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-administration.

Pedunculopontine arousal system physiology-Effects of psychostimulant abuse.

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 betweenNCS-1 and inositol 1,4,5-triphosphate receptor protein (InsP3R).NCS-1 is known to enhance the activity of InsP3R, and of Ca(2+)-mediated gamma oscillatory activity in the pedunculopontine nucleus (PPN), part of theRAS This study aimed to determine the nature of some of the intracellular mechanisms of Li(+)on ratPPNcells and to identify the interaction between Li(+)andNCS-1. Since Li(+)has been shown to act by inhibiting the enhancing effects ofNCS-1, we tested the hypothesis that Li(+)would reduced the effects of overexpression ofNCS-1 and prevent the downregulation of gamma band activity. Li(+)decreased gamma oscillation frequency and amplitude by downregulating Ca(2+)channel activity, whereasNCS-1 reduced the effect of Li(+)on Ca(2+)currents. These effects were mediated by a G-protein overinhibition of Ca(2+)currents. These results suggest that Li(+)affected intracellular pathways involving the activation of voltage-gated Ca(2+)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 byNCS-1.

Stasia D'Onofrio

Center for Translational Neuroscience

University of Arkansas for Medical Sciences

Recording Gamma Band Oscillations in Pedunculopontine Nucleus Neurons

Stasia D'Onofrio

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Center for Translational Neuroscience

University of Arkansas for Medical Sciences

Recording Gamma Band Oscillations in Pedunculopontine Nucleus Neurons

Center for Translational Neuroscience