Activity in the pontine reticular nuclei scales with handgrip force in humans.

The neural pathways that contribute to force production in humans are currently poorly understood, as the relative roles of the corticospinal tract and brainstem pathways, such as the reticulospinal tract (RST), vary substantially across species. Using functional magnetic resonance imaging (fMRI), we aimed to measure activation in the pontine reticular nuclei (PRN) during different submaximal handgrip contractions to determine the potential role of the PRN in force modulation. Thirteen neurologically intact participants (age: 28 ± 6 yr) performed unilateral handgrip contractions at 25%, 50%, 75% of maximum voluntary contraction during brain scans. We quantified the magnitude of PRN activation from the contralateral and ipsilateral sides during each of the three contraction intensities. A repeated-measures ANOVA demonstrated a significant main effect of force (P = 0.012, [Formula: see text] = 0.307) for PRN activation, independent of side (i.e., activation increased with force for both contralateral and ipsilateral nuclei). Further analyses of these data involved calculating the linear slope between the magnitude of activation and handgrip force for each region of interest (ROI) at the individual-level. One-sample t tests on the slopes revealed significant group-level scaling for the PRN bilaterally, but only the ipsilateral PRN remained significant after correcting for multiple comparisons. We show evidence of task-dependent activation in the PRN that was positively related to handgrip force. These data build on a growing body of literature that highlights the RST as a functionally relevant motor pathway for force modulation in humans.NEW & NOTEWORTHY In this study, we used a task-based functional magnetic resonance imaging (fMRI) paradigm to show that activity in the pontine reticular nuclei scales linearly with increasing force during a handgrip task. These findings directly support recently proposed hypotheses that the reticulospinal tract may play an important role in modulating force production in humans.

Pedunculo-pontine tegmentum cholinergic REM-ON neurons modulate ventral tegmental neurons to modulate rapid eye movement sleep in rats.

The interaction among the acetylcholine (ACh)-ergic REM-ON neurons in the pedunculo-pontine area (PPT), noradrenergic REM-OFF neurons in locus coeruleus (LC) and GABA-ergic neurons in the regulation of rapid eye movement sleep (REMS) have been studied in relative details; however, many questions including the role of dopamine (DA) remain unanswered. The ventral tegmental area (VTA) is rich in DA-ergic neurons, which have been implicated with schizophrenia and depression, when REMS is significantly affected. Also, some of the symptoms of REMS and these diseases are common. As the ACh-ergic REM-ON neurons in the PPT project to VTA, we proposed that such inputs might affect REMS, dreams and hallucinations. We recorded sleep-wake-REMS in freely moving, chronically prepared rats under three controlled experimental conditions. In different sets of experiments, either the ACh-ergic inputs to the VTA were blocked by local microinjection of Scopolamine (Scop) alone, or, the PPT neurons were bilaterally stimulated by Glutamate (Glut), or, the PPT neurons were stimulated by Glut in presence of Scop into the VTA. It was observed that Glut into PPT and Scop into the VTA significantly increased and decreased REMS, respectively. Additionally, PPT stimulation induced increased REMS was prevented in the presence of Scop into the VTA. Based on these findings we propose that inputs from ACh-ergic REM-ON neurons to VTA increase REMS and it could be a possible circuitry for expressions of hallucinations and dreams.

Dopaminergic- and cholinergic-inputs from substantia nigra and pedunculo-pontine tegmentum, respectively, converge in amygdala to modulate rapid eye movement sleep in rats.

Dreams appear intermittently during phasic rapid eye movement sleep (REMS). Although reasonable progress has been made about neuro-physio-pharmacological mechanism of appearance of REMS, appearance of dreams is a mystery. Isolated studies have reported that substantia nigra (SN) withdraws inhibition from pedunculo-pontine tegmentum (PPT) acetylcholine (ACh)-ergic REM-ON neurons to trigger REMS; some REM-ON neurons become phasically active during REMS; amygdala (Amyg), a limbic structure associated with emotions, may be related with dreaming like state; Amyg receives projections from both SN-Dopamine (DA)-ergic and PPT-ACh-ergic neurons. Collating these isolated findings, we proposed that on the background of REMS, SN-DA-ergic and PPT-ACh-ergic inputs phasically activate Amyg-neurons to manifest dreams. In the absence of better criteria, we recorded electrophysiological characteristics of REMS as the closest objective read-out for dreams in surgically prepared, chronic, freely moving rats. Microinjection of either DA-ergic or ACh-ergic agonist [Quinpirole (Qnp) or Carbachol (Carb)] bilaterally into Amyg increased, while antagonists [Haloperidol (Hal) or Scopolamine (Scop)] reduced REMS. Electrical stimulation of either bilateral SN or PPT increased REMS, which however, was prevented when stimulated in presence of Hal or Scop, respectively into the Amyg. These findings confirm and support our contention that SN-DA-ergic and PPT-ACh-ergic inputs integrate in Amyg for REMS regulation. Further, subject to confirmation in humans, we propose that on the background of REMS, some phasic PPT-ACh-ergic-REM-ON neurons intermittently trigger some neurons in Amyg, the area known to be associated with memory and emotions, causing intermittent appearance of REMS-associated dreams and in REMS behavior disorder.

Pontine A5 region modulation of the cardiorespiratory response evoked from the midbrain dorsolateral periaqueductal grey.

Connections between the midbrain dorsolateral periaqueductal grey (dlPAG) and the pontine A5 region have been shown. The stimulation of both regions evokes similar cardiovascular responses: tachycardia and hypertension. Accordingly, we have studied the interactions between dlPAG and A5 region in spontaneously breathing anesthetized rats. dlPAG was electrically stimulated (20-30 µA 1-ms pulses were given for 5 s at 100 Hz). Changes in the evoked cardiorespiratoy response were analysed before and after ipsilateral microinjections of muscimol (GABAergic agonist, 50 nl, 0.25 nmol, 5 s) within the A5 region. Electrical stimulation of the dlPAG produces, in the rat, a response characterized by tachypnoea (p < 0.001), hypertension (p < 0.001) and tachycardia (p < 0.001). The increase in respiratory rate was due to a decrease in expiratory time (p < 0.01). Pharmacological inhibition of the A5 region with muscimol produced a marked reduction of the tachycardia (p < 0.001) and the tachypnoea (p < 0.01) evoked from the dlPAG. Finally, to assess functional interactions between A5 and dlPAG, extracellular activity of putative A5 neurones were recorded during dlPAG electrical stimulation. Forty A5 cells were recorded, 16 of which were affected by dlPAG stimulation (40%). 4 cells showed activation, 5 cells excitation and 7 cells decreased spontaneous activity to dlPAG stimulation (p < 0.001). These results confirm a link between the A5 region and dlPAG. The potential role of these connections in the modulation of dlPAG evoked cardiorespiratory responses and their possible clinical implications are discussed.

The Ascending Reticular Activating System.

Discovery of the ascending reticular activating system (ARAS) can be attributed to work done in research neuroscientist Horace Magoun's laboratory. Before this finding, most scientists would focus on the diencephalon (and anterior midbrain) but not more caudally. Stimulation of the medial bulbar reticular formation in the pontine and midbrain tegmentum resulted disappearance of synchronized discharge and low-voltage fast activity. The effects were mediated by a thalamic projection system. This finding was a dramatic departure from the early philosophers' ascription of the awake soul to the ventricles (Galen), lumbosacral cord (Plato), pineal gland (Descartes), and even from more modern nineteenth- and twentieth-century hypotheses that the corpus striatum or periaqueductal gray matter housed the "seat of awareness." Magoun and his collaborators closed in on its true location in the cephalic brainstem-clinicians and neuropathologists would soon follow.

Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders.

Sensory processing, and auditory processing in particular, is altered in individuals with neurodevelopmental disorders such as autism spectrum disorders (ASDs). The typical maturation of the auditory system is perturbed in these individuals during early development, which may underlie altered auditory reactivity that persists in later life. Of the many genes that regulate the auditory system development, loss-of-function mutations in the CNTNAP2 gene are strongly associated with language processing deficits and ASD. Therefore, using a novel Cntnap2 knock-out rat model, we tested the impact of Cntnap2 loss on auditory processing, filtering, and reactivity throughout development and young adulthood in male and female animals. Although hearing thresholds were not altered in Cntnap2 knock-out animals, we found a reduction in response amplitudes and a delay in response latency of the auditory brainstem response (ABR) in juvenile Cntnap2 knock-out rats compared with age-matched controls. Amplitudes and latency of the ABR largely normalized by adulthood, indicating a delayed maturation of auditory processing pathways in Cntnap2 knock-out rats. Despite the reduced ABR amplitudes, adolescent Cntnap2 knock-out animals displayed increased startle reactivity accompanied by disruptions in sensory filtering and sensorimotor gating across various conditions, most of which persisted in adulthood. All of these observations show striking parallels to disruptions reported in ASD. Our results also imply that developmental disruptions of sensory signal processing are associated with persistent changes in neural circuitries responsible for implicit auditory evoked behavior, emphasizing the need for interventions that target sensory processing disruptions early during development in ASD.SIGNIFICANCE STATEMENT This is the first study of brainstem auditory processing in a novel knock-out rat model with very high construct and face validity for autism spectrum disorders. Electrophysiological and behavioral measures of implicit auditory-evoked responses were systematically taken across developmental stages. Auditory processing, filtering, and reactivity disruptions show striking similarities to observations in autism. We also show for the first time that, whereas auditory brainstem responses normalize by adulthood, disruptions in brainstem-mediated auditory-evoked behavior persist. This indicates that early developmental perturbations in sensory processing can cause permanent maladaptive changes in circuitries responsible for auditory reactivity, underlining the importance for interventions early during development aiming at normalizing sensory processing.

Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue-Induced Associative Motor Learning.

Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

Mammillothalamic and Mammillotegmental Tracts as New Targets for Dementia and Epilepsy Treatment.

BACKGROUND: Recently, neuromodulation through deep brain stimulation (DBS) has appeared as a new surgical procedure in the treatment of some types of dementia and epilepsy. The mammillothalamic and mammillotegmental tracts are involved among the new targets. To our knowledge, a review article focused specifically on these mammillary body efferents is lacking in the medical literature. Their contribution to memory is, regrettably, often overlooked. METHODS: A review of the relevant literature was conducted. RESULTS: There is evidence that mammillary bodies can contribute to memory independently from hippocampal formation, but the mechanism is not yet known. Recent studies in animals have provided evidence for the specific roles of these mammillary body efferents in regulating memory independently. In animal studies, it has been shown that the disruption of the mammillothalamic tract inhibits seizures and that electrical stimulation of the mammillary body or mammillothalamic tract raises the seizure threshold. In humans, DBS targeting the mammillary body through the mammillothalamic tract or the stimulation of the anterior thalamic nucleus, especially in the areas closely related to the mammillothalamic tract, has been found effective in patients with medically refractory epilepsy. Nonetheless, little knowledge exists on the functional anatomy of the mammillary body efferents, and their role in the exact mechanism of epileptogenic activity and in the memory function of the human brain. CONCLUSIONS: A comprehensive knowledge of the white matter anatomy of the mammillothalamic and mammillotegmental tracts is crucial since they have emerged as new DBS targets in the treatment of various disorders including dementia and epilepsy.

Neuropeptide S (NPS) is a neuropeptide with cellular actions in arousal and anxiety-related nuclei: Functional implications for effects of NPS on wakefulness and mood.

Neuropeptide S (NPS) is a peptide recently recognized to be present in the CNS, and believed to play a role in vigilance and mood control, as behavioral studies have shown it promotes arousal and has an anxiolytic effect. Although NPS precursor is found in very few neurons, NPS positive fibers are present throughout the brain stem. Given the behavioral actions of this peptide and the wide innervation pattern, we examined the cellular effects of NPS within two brain stem nuclei known to play a critical role in anxiety and arousal: the dorsal raphe (DR) and laterodorsal tegmentum (LDT). In mouse brain slices, NPS increased cytoplasmic levels of calcium in DR and LDT cells. Calcium rises were independent of action potential generation, reduced by low extracellular levels of calcium, attenuated by IP3 - and ryanodine (RyR)-dependent intracellular calcium store depletion, and eliminated by the receptor (NPSR) selective antagonist, SHA 68. NPS also exerted an effect on the membrane of DR and LDT cells inducing inward and outward currents, which were driven by an increase in conductance, and eliminated by SHA 68. Membrane actions of NPS were found to be dependent on store-mediated calcium as depletion of IP3 and RyR stores eliminated NPS-induced currents. Finally, NPS also had actions on synaptic events, suggesting facilitation of glutamatergic and GABAergic presynaptic transmission. When taken together, actions of NPS influenced the excitability of DR and LDT neurons, which could play a role in the anxiolytic and arousal-promoting effects of this peptide.

Change of ascending reticular activating system with recovery from vegetative state to minimally conscious state in a stroke patient.

RATIONALE: We report on a stroke patient who showed change of the ascending reticular activating system (ARAS) concurrent with recovery from a vegetative state (VS) to a minimally conscious state (MCS), which was demonstrated on diffusion tensor tractography (DTT). PATIENT CONCERNS: A 59-year-old male patient underwent CT-guided stereotactic drainage 3 times for management of intracerebral hemorrhage and intraventricular hemorrhage. DIAGNOSIS: After 4 months from onset, when starting rehabilitation, the patient showed impaired consciousness, with a Glasgow Coma Scale (GCS) score of 6 and a Coma Recovery Scale-Revised score of 2. At 10 months after onset, his GCS score had recovered to 11 with a GRS-R score of 20, and he was able to perform rock-scissors-paper using his right hand according to verbal command. INTERVENTIONS: On 10-month DTT, marked increased neural connectivity of the thalamic intralaminar nucleus (ILN) to the cerebral cortex was observed in both prefrontal cortexes and the right thalamus compared with 4-month DTT. However, no significant change was observed in the lower dorsal ARAS between the pontine reticular formation (PRF) and the thalamic ILN. In addition, the reconstructed lower ventral ARAS between the PRF and hypothalamus had disappeared in both hemispheres on 10-month DTT. OUTCOMES: Change of the ARAS was demonstrated in a stroke patient who showed recovery from a VS to an MCS. LESSONS: It appeared that the prefrontal cortex and thalamus, which showed increased neural connectivity, contributed to recovery from a VS to an MCS in this patient.

Calcium imaging of sleep-wake related neuronal activity in the dorsal pons.

The dorsal pons has long been implicated in the generation of rapid eye movement (REM) sleep, but the underlying circuit mechanisms remain poorly understood. Using cell-type-specific microendoscopic Ca(2+) imaging in and near the laterodorsal tegmental nucleus, we found that many glutamatergic neurons are maximally active during REM sleep (REM-max), while the majority of GABAergic neurons are maximally active during wakefulness (wake-max). Furthermore, the activity of glutamatergic neurons exhibits a medio-lateral spatial gradient, with medially located neurons more selectively active during REM sleep.

Our first decade of experience in deep brain stimulation of the brainstem: elucidating the mechanism of action of stimulation of the ventrolateral pontine tegmentum.

The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region.

Pontine reticulospinal projections in the neonatal mouse: Internal organization and axon trajectories.

We recently characterized physiologically a pontine reticulospinal (pRS) projection in the neonatal mouse that mediates synaptic effects on spinal motoneurons via parallel uncrossed and crossed pathways (Sivertsen et al. [2014] J Neurophysiol 112:1628-1643). Here we characterize the origins, anatomical organization, and supraspinal axon trajectories of these pathways via retrograde tracing from the high cervical spinal cord. The two pathways derive from segregated populations of ipsilaterally and contralaterally projecting pRS neurons with characteristic locations within the pontine reticular formation (PRF). We obtained estimates of relative neuron numbers by counting from sections, digitally generated neuron position maps, and 3D reconstructions. Ipsilateral pRS neurons outnumber contralateral pRS neurons by threefold and are distributed about equally in rostral and caudal regions of the PRF, whereas contralateral pRS neurons are concentrated in the rostral PRF. Ipsilateral pRS neuron somata are on average larger than contralateral. No pRS neurons are positive in transgenic mice that report the expression of GAD, suggesting that they are predominantly excitatory. Putative GABAergic interneurons are interspersed among the pRS neurons, however. Ipsilateral and contralateral pRS axons have distinctly different trajectories within the brainstem. Their initial spinal funicular trajectories also differ, with ipsilateral and contralateral pRS axons more highly concentrated medially and laterally, respectively. The larger size and greater number of ipsilateral vs. contralateral pRS neurons is compatible with our previous finding that the uncrossed projection transmits more reliably to spinal motoneurons. The information about supraspinal and initial spinal pRS axon trajectories should facilitate future physiological assessment of synaptic connections between pRS neurons and spinal neurons.

Second tectofugal pathway in a songbird (Taeniopygia guttata) revisited: Tectal and lateral pontine projections to the posterior thalamus, thence to the intermediate nidopallium.

Birds are almost always said to have two visual pathways from the retina to the telencephalon: thalamofugal terminating in the Wulst, and tectofugal terminating in the entopallium. Often ignored is a second tectofugal pathway that terminates in the nidopallium medial to and separate from the entopallium (e.g., Gamlin and Cohen [1986] J Comp Neurol 250:296-310). Using standard tract-tracing and electroanatomical techniques, we extend earlier evidence of a second tectofugal pathway in songbirds (Wild [1994] J Comp Neurol 349:512-535), by showing that visual projections to nucleus uvaeformis (Uva) of the posterior thalamus in zebra finches extend farther rostrally than to Uva, as generally recognized in the context of the song control system. Projections to "rUva" resulted from injections of biotinylated dextran amine into the lateral pontine nucleus (PL), and led to extensive retrograde labeling of tectal neurons, predominantly in layer 13. Injections in rUva also resulted in extensive retrograde labeling of predominantly layer 13 tectal neurons, retrograde labeling of PL neurons, and anterograde labeling of PL. It thus appears that some tectal neurons could project to rUva and PL via branched axons. Ascending projections of rUva terminated throughout a visually responsive region of the intermediate nidopallium (NI) lying between the nucleus interface medially and the entopallium laterally. Lastly, as shown by Clarke in pigeons ([1977] J Comp Neurol 174:535-552), we found that PL projects to caudal cerebellar folia.

[EFFECTS OF ELECTRICAL STIMULATION OF NUCLEUS RETICULARIS PONTIS ORALIS ON THE SLEEP-WAKING STATES IN KRUSHINSKII-MOLODKINA STRAIN RATS].

The effects of electrical stimulation of nucleus reticularis pontis oralis on the behavior and brain electrical activity during all phases of the sleep-waking cycle was studied in Krushinskii-Molodkina strain rats, which have an inherited predisposition to audiogenic seizures. Electrical stimulation with 7 Hz frequency in the deep stage of slow-wave sleep cause appearance the fast-wave sleep. Similar stimulation during fast-wave sleep periods did not effects on the electrographic patterns and EEG spectral characteristics of hippocampus, visual, auditory and somatocnen nrnrenc nf the cnrtey ThPe sfimul1stinns did nnt break a fast-wave sleenhut increased almost twice due the duration of these sleep episodes. After electrical stimulation by same frequency during the wakeftlness and superficial slow-wave sleep states, the patterns and spectral characteristics of brain electrical activity in rats showed no significant changes as compared with controls. The results of this study indicate that the state of the animals sleep-waking cycle at the time of stimulation is a critical variable that influences the responses which are induced by electrical stimulation of the nucleus reticularis pontis oralis.

Paradoxical (rapid eye movement) sleep-on neurons in the laterodorsal pontine tegmentum in mice.

A total of 211 neurons that discharged at the highest rate during sleep (sleep-active neurons) were recorded in non-anesthetized, head-restrained mice during the complete wake-sleep cycle in, and around, the laterodorsal (LDT) and sublaterodorsal (SubLDT) tegmental nuclei, which contain both cholinergic and non-cholinergic neurons. For the first time in mice, I reveal the presence, mainly in the SubLDT, of sleep-specific neurons displaying sustained tonic discharge either (i) just prior to, and during, paradoxical sleep (PS) (PS-on neurons) or (ii) during both slow-wave sleep (SWS) and PS (SWS/PS-on neurons). Both the PS-on and SWS/PS-on neurons showed either a low (< 10 Hz) or high (⩾ 10 Hz) rate of spontaneous firing and exhibited a biphasic narrow or medium-to-broad action potential, a characteristic of non-cholinergic neurons. At the transition from SWS to waking (W), the PS-on and SWS/PS-on neurons simultaneously ceased firing shortly before the onset of W, whereas, at the transition from W to SWS, only the SWS/PS-on neurons fired shortly after the onset of sleep. At the transition from SWS to PS, only the PS-on neurons exhibited a significant increase in discharge rate before PS onset, while, at the transition from PS to W, the SWS/PS-on neurons, then the PS-on neurons, displayed a significant decrease in the discharge rate before the end of PS. The SWS/PS-on neurons were more sensitive to the change in the electroencephalogram (EEG) than the PS-on neurons, as, during a PS episode, the slightest interruption of rhythmic theta activity resulted in cessation of discharge of the SWS/PS-on neurons. These findings support the view that, in the mouse SubLDT, PS-on neurons play an important role in the induction, maintenance, and cessation of PS, while SWS/PS-on neurons play a role in the maintenance of the PS state in particular and the sleep state in general.

REM sleep modulation by perifornical orexinergic inputs to the pedunculo-pontine tegmental neurons in rats.

Rapid eye movement sleep (REMS) is regulated by the interaction of the REM-ON and REM-OFF neurons located in the pedunculo-pontine-tegmentum (PPT) and the locus coeruleus (LC), respectively. Many other brain areas, particularly those controlling non-REMS (NREMS) and waking, modulate REMS by modulating these REMS-related neurons. Perifornical (PeF) orexin (Ox)-ergic neurons are reported to increase waking and reduce NREMS as well as REMS; dysfunction of the PeF neurons are related to REMS loss-associated disorders. Hence, we were interested in understanding the neural mechanism of PeF-induced REMS modulation. As a first step we have recently reported that PeF Ox-ergic neurons modulate REMS by influencing the LC neurons (site for REM-OFF neurons). Thereafter, in this in vivo study we have explored the role of PeF inputs on the PPT neurons (site for REM-ON neurons) for the regulation of REMS. Chronic male rats were surgically prepared with implanted bilateral cannulae in PeF and PPT and electrodes for recording sleep-waking patterns. After post-surgical recovery sleep-waking-REMS were recorded when bilateral PeF neurons were stimulated by glutamate and simultaneously bilateral PPT neurons were infused with either saline or orexin receptor1 (OX1R) antagonist. It was observed that PeF stimulation increased waking and decreased NREMS as well as REMS, which were prevented by OX1R antagonist into the PPT. We conclude that the PeF stimulation-induced reduction in REMS was likely to be due to inhibition of REM-ON neurons in the PPT. As waking and NREMS are inversely related, subject to confirmation, the reduction in NREMS could be due to increased waking or vice versa. Based on our findings from this and earlier studies we have proposed a model showing connections between PeF- and PPT-neurons for REMS regulation.

Bilateral force transients in the upper limbs evoked by single-pulse microstimulation in the pontomedullary reticular formation.

Neurons in the pontomedullary reticular formation (PMRF) give rise to the reticulospinal tract. The motor output of the PMRF was investigated using stimulus-triggered averaging of electromyography (EMG) and force recordings in two monkeys (M. fascicularis). EMG was recorded from 12 pairs of upper limb muscles, and forces were detected using two isometric force-sensitive handles. Of 150 stimulation sites, 105 (70.0%) produced significant force responses, and 139 (92.5%) produced significant EMG responses. Based on the average flexor EMG onset latency of 8.3 ms and average force onset latency of 15.9 ms poststimulation, an electromechanical delay of ∼7.6 ms was calculated. The magnitude of force responses (∼10 mN) was correlated with the average change in EMG activity (P < 0.001). A multivariate linear regression analysis was used to estimate the contribution of each muscle to force generation, with flexors and extensors exhibiting antagonistic effects. A predominant force output pattern of ipsilateral flexion and contralateral extension was observed in response to PMRF stimulation, with 65.3% of significant ipsilateral force responses directed medially and posteriorly (P < 0.001) and 78.6% of contralateral responses directed laterally and anteriorly (P < 0.001). This novel approach permits direct measurement of force outputs evoked by central nervous system microstimulation. Despite the small magnitude of poststimulus EMG effects, low-intensity single-pulse microstimulation of the PMRF evoked detectable forces. The forces, showing the combined effect of all muscle activity in the arms, are consistent with reciprocal pattern of force outputs from the PMRF detectable with stimulus-triggered averaging of EMG.

The ascending reticular activating system from pontine reticular formation to the hypothalamus in the human brain: a diffusion tensor imaging study.

The ascending reticular activating system (ARAS) is responsible for regulation of consciousness. Precise evaluation of the ARAS is important for diagnosis and management of patients with impaired consciousness. In the current study, we attempted to reconstruct the portion of the ARAS from the pontine reticular formation (RF) to the hypothalamus in normal subjects, using diffusion tensor imaging (DTI). A total of 31 healthy subjects were recruited for this study. DTI scanning was performed using 1.5-T, and the ARAS from the pontine RF to the hypothalamus was reconstructed. Values of fractional anisotropy, mean diffusivity, and tract volume of the ARAS from the pontine RF to the hypothalamus were measured. In all subjects, the ARAS from the pontine RF to the hypothalamus originated from the RF at the level of the mid-pons, where the trigeminal nerve could be seen, ascended through the periaqueductal gray matter of the midbrain anterolaterally to the anterior commissure level, and then terminated into the hypothalamus. No significant differences in DTI parameters were observed between the left and right hemispheres and between males and females (p<0.05). We identified the ARAS between the pontine RF and the hypothalamus in normal subjects using DTI. We believe that the reconstruction methodology and the results of this study would be useful to clinicians involved in the care of patients with impaired consciousness and researchers in studies of the ARAS.

A subcortical inhibitory signal for behavioral arrest in the thalamus.

Organization of behavior requires rapid coordination of brainstem and forebrain activity. The exact mechanisms of effective communication between these regions are presently unclear. The intralaminar thalamic nuclei (IL) probably serves as a central hub in this circuit by connecting the critical brainstem and forebrain areas. We found that GABAergic and glycinergic fibers ascending from the pontine reticular formation (PRF) of the brainstem evoked fast and reliable inhibition in the IL via large, multisynaptic terminals. This inhibition was fine-tuned through heterogeneous GABAergic and glycinergic receptor ratios expressed at individual synapses. Optogenetic activation of PRF axons in the IL of freely moving mice led to behavioral arrest and transient interruption of awake cortical activity. An afferent system with comparable morphological features was also found in the human IL. These data reveal an evolutionarily conserved ascending system that gates forebrain activity through fast and powerful synaptic inhibition of the IL.