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The frontal lobe is crucial and contributes to controlling truncal motion, postural responses, and maintaining equilibrium and locomotion. The rich repertoire of frontal gait disorders gives some indication of this complexity. For human walking, it is necessary to simultaneously achieve at least two tasks, such as maintaining a bipedal upright posture and locomotion. Particularly, postural control plays an extremely significant role in enabling the subject to maintain stable gait behaviors to adapt to the environment. To achieve these requirements, the frontal cortex (1) uses cognitive information from the parietal, temporal, and occipital cortices, (2) creates plans and programs of gait behaviors, and (3) acts on the brainstem and spinal cord, where the core posture-gait mechanisms exist. Moreover, the frontal cortex enables one to achieve a variety of gait patterns in response to environmental changes by switching gait patterns from automatic routine to intentionally controlled and learning the new paradigms of gait strategy via networks with the basal ganglia, cerebellum, and limbic structures. This chapter discusses the role of each area of the frontal cortex in behavioral control and attempts to explain how frontal lobe controls walking with special reference to postural control., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Growing evidence indicates that visceral hypersensitivity and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). In animal models, these changes are known to be mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4 (TLR4)-proinflammatory cytokine signaling. Apelin, an endogenous ligand of APJ, was reported to modulate CRF-induced enhanced colonic motility. In this context, we hypothesized that apelin also modulates visceral sensation and gut barrier, and tested this hypothesis. We measured visceral pain threshold in response to colonic balloon distention by abdominal muscle contractions assessed by electromyogram in rats. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal (ip) administration of [Ala13]-apelin-13, an APJ antagonist, blocked lipopolysaccharide (LPS)- or CRF-induced visceral hypersensitivity and colonic hyperpermeability (IBS model) in a dose-response manner. These inhibitory effects were blocked by compound C, an AMPK inhibitor, N G -nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor or naloxone in the LPS model. On the other hand, ip [Pyr1]-apelin-13, an APJ agonist, caused visceral hypersensitivity and colonic hyperpermeability, and these effects were reversed by astressin, a CRF receptor antagonist, TAK-242, a TLR4 antagonist or anakinra, an interleukin-1 receptor antagonist. APJ system modulated CRF-TLR4-proinflammatory cytokine signaling to cause visceral hypersensitivity and colonic hyperpermeability. APJ antagonist blocked these GI changes in IBS models, which were mediated via AMPK, NO and opioid signaling. Apelin may contribute to the IBS pathophysiology, and the inhibition of apelinergic signaling may be a promising therapeutic option for IBS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We have recently demonstrated that orexin acts centrally through the brain orexin 1 receptors to induce an antinociceptive action against colonic distension in conscious rats. Adenosine signaling is capable of inducing an antinociceptive action against somatic pain; however, the association between changes in the adenosinergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the adenosinergic system may be involved in visceral nociception, and thus, adenosine signaling may mediate orexin-induced visceral antinociception. Visceral sensation was evaluated based on the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneous (0.04-0.2mg/rat) or intracisternal (0.8-4μg/rat) injection of N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor (A1R) agonist, increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner, thereby suggesting that CPA acts centrally in the brain to induce an antinociceptive action against colonic distension. Pretreatment with theophylline, an adenosine antagonist, or 1,3-dipropyl-8-cyclopentylxanthine, an A1R antagonist, subcutaneously injected potently blocked the centrally injected CPA- or orexin-A-induced antinociceptive action against colonic distension. These results suggest that adenosinergic signaling via A1Rs in the brain induces visceral antinociception and that adenosinergic signaling is involved in the central orexin-induced antinociceptive action against colonic distension., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Posture control to maintain an upright stance is one of the most important and basic requirements in the daily life of humans. The sensory inputs involved in posture control include visual and vestibular inputs, as well as proprioceptive and tactile somatosensory inputs. These multisensory inputs are integrated to represent the body state (body schema); this is then utilized in the brain to generate the motion. Changes in the multisensory inputs result in postural alterations (fast dynamics), as well as long-term alterations in multisensory integration and posture control itself (slow dynamics). In this review, we discuss the fast and slow dynamics, with a focus on multisensory integration including an introduction of our study to investigate "internal force control" with multisensory integration-evoked posture alteration. We found that the study of the slow dynamics is lagging compared to that of fast dynamics, such that our understanding of long-term alterations is insufficient to reveal the underlying mechanisms and to propose suitable models. Additional studies investigating slow dynamics are required to expand our knowledge of this area, which would support the physical training and rehabilitation of elderly and impaired persons., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

To understand the role of cholinoceptive, medial pontine reticular formation (mPRF) neurons in the control of upper airway, pharyngolaryngeal reflexes, we measured activities of intrinsic laryngeal muscles (posterior cricoarytenoid, PCA; thyroarytenoid, TA), diaphragm (DIA), genioglossus (GG) and a neck muscle (trapezius) in unanesthetized, decerebrated, spontaneously breathing cats with and without mPRF carbachol injections. The ethimoidal nerve was electrically stimulated to evoke sneezing, and the superior laryngeal nerve to evoke the laryngeal reflex, swallowing, and coughing. Carbachol reduced the amplitudes of the spontaneous electromyographic activities in the neck, TA, PCA, GG, and DIA to 7%, 30%, 54%, 45% and 71% of control, respectively, reduced the respiratory rate to 53% without changes in expiratory CO(2) concentration; the magnitude of the laryngeal reflex in the TA muscle to 56%; increased its latency by 13%; and reduced the probability of stimulus-induced sneezing, swallowing, and coughing to less than 40%. These changes lasted more than 1h. These data demonstrate that important upper airway reflexes are suppressed by increasing cholinergic neurotransmission in the mPRF. Because acetylcholine release in the mPRF changes in accordance with sleep-wake cycles, the present findings are relevant to the control of upper airway reflexes during various vigilance states., (2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Lipin-1 is a multifunctional metabolic regulator, involving in triacylglycerol and bioactive glycerolipids synthesis as an enzyme, transcriptional regulation as a coactivator, and adipogenesis. In obesity, adipose lipin-1 expression is decreased. Although lipin-1 is implicated in the pathogenesis of obesity, the mechanism is still not clear. Since TNF-alpha is deeply involved in the pathogenesis of obesity, insulin resistance, and diabetes, here we investigated the role of TNF-alpha on lipin-1 expression in adipocytes. Quantitative PCR studies showed that TNF-alpha suppressed both lipin-1A and -1B isoform expression in time- and dose-dependent manners in mature 3T3-L1 adpocytes. A Jak2 inhibitor, AG490, reversed the suppressive effect of TNF-alpha on both lipin-1A and -1B. In contrast, NF-kappaB, MAPKs, ceramide, and beta-catenin pathway tested were not involved in the mechanism. These results suggest that TNF-alpha could be involved in obesity-induced lipin-1 suppression in adipocytes and Jak2 may play an important role in the mechanism.

We examined the effects of troglitazone on expression of E-cadherin and claudin 4 in human pancreatic cancer cells. Troglitazone dose-dependently increased expression of E-cadherin and claudin 4 mRNA and protein in PK-1 cells. Snail, Slug and ZEB1, mRNAs were not changed by troglitazone, indicating that these three transcriptional repressors would not play a role in the induction of E-cadherin by troglitazone. GW9662, a PPARgamma antagonist, failed to block the increased expression of E-cadherin or claudin 4 mRNA, suggesting a PPARgamma-independent pathway. A MEK inhibitor, U0126, increased E-cadherin or claudin 4 mRNA and protein expression, and potently inhibited cell invasion. Because troglitazone down-regulates MEK-ERK signaling and inhibit cell invasion in PK-1 as shown in our previous study, these results suggest that troglitazone increases expression of E-cadherin and claudin 4 possibly through inhibition of MEK-ERK signaling in pancreatic cancer cells, which might be involved in the troglitazone-induced inhibition of cell invasive activity.

The purpose of this study was to elucidate the role of the GABAergic system in the medullary reticular formation (MRF) in the control of swallowing. In acutely decerebrated cats (n = 12), swallowing was induced by electrical stimulation (0.3-6 V at 10-20 Hz for 10-20 s every minute) applied to the superior laryngeal nerve (SLN). The stimulus intensity was adjusted so that swallowing was induced two or four times during the period of the stimulation. Bicuculline, a GABA(A) receptor antagonist, was then injected (0.10-0.15 microl, 5 mM) into the MRF through a stereotaxically placed glass micropipette. In a total of 62 injections, 19 injections (30.6%) increased the frequency of SLN-induced swallowing when it was injected into the lateral part of the MRF corresponding to the nucleus reticularis parvocellularis (NRPv). In eight of the effective injections (42.1%) which increased the frequency of SLN-induced swallowing, SLN stimulation also induced coughing. With two injections, stimulation of the SLN-induced coughing but not facilitation of swallowing. On the other hand, an injection of 0.10-0.15 microl of 5 mM muscimol, a GABA(A) receptor agonist, into the NRPv decreased the frequency of SLN-induced swallowing. These results suggest that the NRPv neurons which are responsible for evoking swallowing are under the tonic inhibitory control of the GABAergic system.

Here we review a role of a basal ganglia-brainstem (BG-BS) system throughout the mesopontine tegmentum in the control of various types of behavioral expression. First the basal ganglia-brainstem system may contribute to an automatic control of movements, such as rhythmic limb movements and adjustment of postural muscle tone during locomotion, which occurs in conjunction with voluntary control processes. Second, the basal ganglia-brainstem system can be involved in the regulation of awake-sleep states. We further propose the possibility that the basal ganglia-brainstem system is responsible for the integration of volitionally-guided and emotionally-triggered expression of motor behaviors. It can be proposed that dysfunction of the basal ganglia-brainstem system together with that of cortico-basal ganglia loop underlies the pathogenesis of behavioral disturbances expressed in basal ganglia dysfunction.

This chapter argues that a basal ganglia-brainstem system throughout the mesopontine tegmentum contributes to an automatic control of movement that operates in conjunction with voluntary control processes. Activity of a muscle tone inhibitory system and the locomotion executing system can be steadily balanced by a net excitatory cortical input and a net inhibitory basal ganglia input to these systems. We further propose that dysfunction of the basal ganglia-brainstem system, together with that of the cortico-basal ganglia loop, underlies the pathogenesis of motor disturbances expressed in basal ganglia diseases.

In acute decerebrate cats, medial pontine reticular formation (mPRF) and the mesencephalic locomotor region (MLR) were stimulated and their stimulus effects upon 250 medullary reticulospinal neurons (RSNs) were studied. One hundred and twenty-six RSNs were mono- and disynaptically activated. From the response patterns of the RSNs, they were divided into the mPRF-activated RSNs (n = 67) and the MLR-activated RSNs (n = 59). The former group of RSNs was located in the nucleus reticularis gigantocellularis (NRGc), while the latter group of RSNs was distributed in both the NRGc and the nucleus reticularis magnocellularis (NRMc). The activity of MLR-excited 12 RSNs was suppressed with the preceding mPRF stimulation. These RSNs were mainly located in the NRMc. Most mPRF-excited RSNs increased their discharge rates during mPRF-evoked suppression of postural muscle tone, and most MLR-excited RSNs increased their discharge rates during MLR-evoked locomotion. With mPRF stimulation, MLR-evoked locomotion was suppressed with cessation of MLR-excited RSNs activity. These results suggest that mPRF stimulation suppresses the activity of the locomotor rhythm generating system at the levels of not only the spinal cord but also the medullary output cells.

Postsynaptic responses of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) to stimulation of the pedunculopontine tegmental nuclei (PPN) were studied in in vitro slice preparations in the rat. The recorded neurons were intracellularly injected with biocytin and also identified as DA neurons by an immunocytochemical technique. PPN stimulation induced in DA neurons monosynaptic excitatory postsynaptic potentials (EPSPs) that consisted of early transient and slow components. An application of anti-glutamatergic agents (1 mM kynurenic acid and/or 30 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)) in the bathing media partially suppressed the EPSPs, indicating that PPN inputs to SNc DA neurons are glutamatergic and non-glutamatergic. Anti-glutamatergic resistant EPSPs were suppressed by applications of anti-cholinergic agents such as atropine, mecamylamine, and pirenzepine. These data indicate a convergence of glutamatergic and cholinergic excitatory inputs from the PPN to SNc DA neurons and that both nicotinic and muscarinic receptors are involved in the cholinergic transmission.

By utilizing an anterograde neural tracer, Phaseolus vulgaris leucoagglutinin (PHA-L), pontomedullary reticuloreticular connections and reticulospinal connections were studied, including their fiber trajectories and distribution of PHA-L labeled terminals in close apposition to target reticular and spinal neurons, and branching patterns of axon collaterals at the levels of the cervical and upper thoracic cord. PHA-L was focally microinjected into the medial pontine reticular formation corresponding to the nucleus reticularis pontis oralis. A great number of PHA-L labeled thin fibers descended bilaterally coursing through the medial part of the pontine and medullary reticular formation with an ipsilateral predominance. Labeled terminal boutons were closely apposed to somata of various sized pontomedullary reticular neurons. Labeled thick fibers descended ipsilaterally coursing through the ventral half of the medial longitudinal fasciculus, and further descended through the ventral funiculus of the spinal cord. At the levels of the cervical and upper thoracic cord, these reticulospinal fibers gave off axon collaterals sending terminal fibers to small- to large-sized neurons in Rexed's laminae VII and VIII. Some of the axon collaterals innervated not only ipsilateral but also contralateral gray matter. By reconstructing branching patterns of axon collaterals, each axon collateral was found to innervate spinal neurons located in a disk-like spinal segment with a width less than 1 mm.

Studies in both decerebrate, and intact cats have already established the presence of specific areas in the brainstem that subserve control of posture and locomotion. They are the subthalamic locomotor region (SLR) in the lateral hypothalamic area (LHA), the mesencephalic locomotor region (MLR) in the posterior midbrain, the dorsal tegmental field (DTF) and the ventral tegmental field (VTF) of caudal pons along its midline. These areas can be stimulates either electrically or chemically to induce site-specific changes in posture and locomotor synergies. Our observations indicate that the postural and locomotor synergies are structured in a hierarchy within rostro-caudal axis of the brainstem, and that the command routing through the brainstem relies on interactions with the SLR, the MLR, the DTF area and the VTF area. These results and our concepts for postural and locomotor control and their interactions are discussed with the concepts of command hierarchies for motor control.