The pedunculopontine nucleus: From posture and locomotion to neuroepigenetics.

In this review, we discuss first an example of one of the symptoms of PD, freezing of gait (FOG), then we will turn to the use of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) to treat PD, and the original studies that led to identification of the PPN as one source of locomotor control and why stimulation frequency is critical, and then describe the intrinsic properties of PPN neurons that require beta/gamma stimulation in order to fully activate all types of PPN neurons. Finally, we will describe recent findings on the proteomic and molecular consequences of gamma band activity in PPN neurons, with emphasis on the potential neuroepigenetic sequelae. These considerations will provide essential information for the appropriate refining and testing of PPN DBS as a potential therapy for PD, as well as alternative options.

Implications of gamma band activity in the pedunculopontine nucleus.

The fact that the pedunculopontine nucleus (PPN) is part of the reticular activating system places it in a unique position to modulate sensory input and fight-or-flight responses. Arousing stimuli simultaneously activate ascending projections of the PPN to the intralaminar thalamus to trigger cortical high-frequency activity and arousal, as well as descending projections to reticulospinal systems to alter posture and locomotion. As such, the PPN has become a target for deep brain stimulation for the treatment of Parkinson's disease, modulating gait, posture, and higher functions. This article describes the latest discoveries on PPN physiology and the role of the PPN in a number of disorders. It has now been determined that high-frequency activity during waking and REM sleep is controlled by two different intracellular pathways and two calcium channels in PPN cells. Moreover, there are three different PPN cell types that have one or both calcium channels and may be active during waking only, REM sleep only, or both. Based on the new discoveries, novel mechanisms are proposed for insomnia as a waking disorder. In addition, neuronal calcium sensor protein-1 (NCS-1), which is over expressed in schizophrenia and bipolar disorder, may be responsible for the dysregulation in gamma band activity in at least some patients with these diseases. Recent results suggest that NCS-1 modulates PPN gamma band activity and that lithium acts to reduce the effects of over expressed NCS-1, accounting for its effectiveness in bipolar disorder.

Gamma band activity in the RAS-intracellular mechanisms.

Gamma band activity participates in sensory perception, problem solving, and memory. This review considers recent evidence showing that cells in the reticular activating system (RAS) exhibit gamma band activity, and describes the intrinsic membrane properties behind such manifestation. Specifically, we discuss how cells in the mesopontine pedunculopontine nucleus, intralaminar parafascicular nucleus, and pontine SubCoeruleus nucleus dorsalis all fire in the gamma band range when maximally activated, but no higher. The mechanisms involve high-threshold, voltage-dependent P/Q-type calcium channels, or sodium-dependent subthreshold oscillations. 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. We address three necessary next steps resulting from these discoveries: an intracellular mechanism responsible for maintaining gamma band activity based on persistent G-protein activation, separate intracellular pathways that differentiate between gamma band activity during waking versus during REM sleep, and an intracellular mechanism responsible for the dysregulation in gamma band activity in schizophrenia. These findings open several promising research avenues that have not been thoroughly explored. What are the effects of sleep or REM sleep deprivation on these RAS mechanisms? Are these mechanisms involved in memory processing during waking and/or during REM sleep? Does gamma band processing differ during waking versus REM sleep after sleep or REM sleep deprivation?

Tolerance to the sedative effect of lorazepam correlates with a diminution in cortical release and affinity for glutamate.

Benzodiazepines are anxiolytic, anticonvulsant, sedative and hypnotic compounds usually prescribed on a long-term basis. Chronic treatment with these compounds induces tolerance, which has been extensively attributed to modifications in the GABAergic neurotransmission. However, a compensatory increase in the excitatory response, named as an oppositional response, has also been put forward as a means for explaining such tolerance. Changes in the excitatory neurotransmission have been found in withdrawn rats after a long treatment with benzodiazepines but these modifications have not been conclusively studied during tolerance. In this work we studied several parameters of the glutamatergic neurotransmission in rats made tolerant to the sedative effect of 3 mg/kg (i.p.) of lorazepam (LZ). We found a decrease in the affinity of cortical NMDA receptors for (3)H-glutamate (K(D): 124.4 +/- 13.3 nM in tolerant rats, 71.6 +/- 10.4 nM in controls, P<0.05) together with a decrease in the in vitro 60 mM K(+)-stimulated cortical glutamate release (59+/- 12% vs. 153 +/- 38%, tolerant rats vs. controls, P<0.05). We conclude that tolerance to the sedative effect of LZ correlates with a decreased sensitivity for glutamate that may in turn diminish the cortical response to a chemical stimulus. Our findings constitute an evidence against the oppositional model of pharmacodynamic tolerance in this experimental condition.

Diazepam fails to potentiate GABA-induced chloride uptake and to produce anxiolytic-like action in aged rats.

The pharmacological response to benzodiazepines has been demonstrated to be different in aged individuals in comparison to adults. We studied the age-dependent changes in some of the in vitro and behavioral effects of diazepam in aged (24 months old) rats, comparing them to adults (3 months old). We evaluated the in vitro gamma-aminobutyric acid (GABA)-induced 36Cl- uptake and the diazepam potentiation of GABA-stimulated 36Cl- uptake in microsacs from cerebral cortex of both groups of animals. We found no differences in the GABA-stimulated 36Cl- uptake between adult and aged animals, and diazepam failed to potentiate GABA-induced 36Cl- flux in the aged cortical microsacs. We also examined the effect of 0.03-10 mg of diazepam on locomotor activity in an open-field test and the anxiolytic-like action of diazepam in doses ranging from 0.03 to 1 in a dark-light transition test. We observed no anxiolytic-like action of the drug in the dark-light transition test in the aged rats, while there was a shift to the left in the diminution of locomotor activity evaluated by the open-field test. We conclude that the pharmacodynamic changes observed in cortical GABA(A) receptors in aged rats could partially explain the lack of anxiolytic-like action but not the oversedation evidenced in this group of animals.

Chronic corticosterone impairs inhibitory avoidance in rats: possible link with atrophy of hippocampal CA3 neurons.

The aim of our work was to evaluate the effect of a chronic (22 days) administration of corticosterone, which induces supraphysiological serum levels of the hormone, on an inhibitory avoidance learning in rats (one-trial step-through learning task, footshock: 0.5 mA, 2 s). We also studied hippocampal markers of neuroanatomical CA3 pyramidal neuron atrophy by using the Golgi staining method. Chronic exposure to high CORT serum levels induced a significant impairment of inhibitory avoidance learning. The CORT group also showed hippocampal glucocorticoid receptor (GR) downregulation and the decrease of hippocampal CA3 branch points and total dendritic length in the apical tree that would be causally related with the learning impairment.