Altered tongue muscle contractile properties coincide with altered swallow function in the adult Ts65Dn mouse model of down syndrome.

Purpose: Down syndrome (DS) is a developmental disability associated with difficulties in deglutition. The adult Ts65Dn mouse model of DS has been previously shown to have differences in measures of swallowing compared with euploid controls. However, the putative mechanisms of these differences in swallowing function are unclear. This study tested the hypothesis that the Ts65Dn genotype is associated with atypical measures of tongue muscle contractile properties, coinciding with atypical swallow function. Methods: Adult (5-month-old) Ts65Dn (n = 15 female, 14 male) and euploid sibling controls (n = 16 female, 14 male) were evaluated through videofluoroscopy swallow studies (VFSS) to quantify measures of swallowing performance including swallow rate and inter-swallow interval (ISI). After VFSS, retrusive tongue muscle contractile properties, including measures of muscle fatigue, were determined using bilateral hypoglossal nerve stimulation. Results: The Ts65Dn group had significantly slower swallow rates, significantly greater ISI times, significantly slower rates of tongue force development, and significantly greater levels of tongue muscle fatigue, with lower retrusive tongue forces than controls in fatigue conditions. Conclusion: Tongue muscle contractile properties are altered in adult Ts65Dn and coincide with altered swallow function.

Tongue and laryngeal exercises improve tongue strength and vocal function outcomes in a Pink1-/- rat model of early Parkinson disease.

Parkinson disease (PD) causes voice and swallow dysfunction even in early stages of the disease. Treatment of this dysfunction is limited, and the neuropathology underlying this dysfunction is poorly defined. Targeted exercise provides the greatest benefit for offsetting voice and swallow dysfunction, and previous data suggest the hypoglossal nucleus and noradrenergic-locus coeruleus (LC) may be involved in its early pathology. To investigate relationships between targeted exercise and neuropathology of voice and swallow dysfunction, we implemented a combined exercise paradigm that included tongue force and vocalization exercises early in the Pink1-/- rat model. We tested the hypotheses that (1) tongue and vocal exercise improves tongue force and timing behaviors and vocalization outcomes, and (2) exercise increases optical density of serotonin (5-HT) in the hypoglossal nucleus, and tyrosine hydroxylase immunoreactive (Th-ir) cell counts in the LC. At two months of age Pink1-/- rats were randomized to exercise or non-exercise treatment. Age-matched wildtype (WT) control rats were assigned to non-exercise treatment. Tongue force and timing behaviors and ultrasonic vocalizations were measured at baseline (two months) and final (four months) timepoints. Optical density of 5-HT in the hypoglossal nucleus and TH-ir cell counts in the LC were obtained. Pink1-/- rats produced greater tongue forces, faster tongue contraction, and higher-intensity vocalization following exercise. There were no differences in LC TH-ir. The non-exercised Pink1-/- group had reduced density of 5-HT in the hypoglossal nucleus compared to the WT control group. The changes to tongue function and vocalization after targeted exercise suggests exercise intervention may be beneficial in early PD.

Age-related sex differences in tongue strength and muscle morphometry in a rat model.

OBJECTIVE: To investigate potential effects of sex on voluntary tongue strength, evoked twitch and tetanic tension, speed of contraction, and muscle fiber cross-sectional area in the muscles of the rat tongue. Additionally, we aimed to determine whether estrous cycle stage impacts any of the dependent variables as a pilot investigation into the use of female rats in a model of tongue exercise and aging. DESIGN: Fischer 344-Brown Norway male and female rats in two age groups (16 middle-aged, 16 young-adult) were trained to use a tongue force operandum. Tongue muscle contraction, myosin heavy chain (MyHC) composition, and cross section area of the genioglossus and styloglossus muscles were examined. Vaginal lavage determined estrous cycle stage of the female rats daily. RESULTS: The female group had significantly lower evoked twitch and tetanic tension, longer contraction times, and a smaller proportion of MyHC type IIa and MyHC type IIx in the styloglossus muscle. There was no significant sex effect in maximal voluntary tongue force (MVTF) despite a significant weight difference between the male and female groups. There were no significant age or sex effects in the genioglossus. Estrous cycle stage did not have a significant effect on any of the dependent variables. CONCLUSIONS: Sex and age both have a significant effect on tongue muscle structure and physiology. While the female group showed reduced contraction speed and maximal twitch and tetanic tension relative to the male group, differences in muscle morphology appeared to vary by muscle.

Early ultrasonic vocalization deficits and related thyroarytenoid muscle pathology in the transgenic TgF344-AD rat model of Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurologic disease and the most common cause of dementia. Classic pathology in AD is characterized by inflammation, abnormal presence of tau protein, and aggregation of ß-amyloid that disrupt normal neuronal function and lead to cell death. Deficits in communication also occur during disease progression and significantly reduce health, well-being, and quality of life. Because clinical diagnosis occurs in the mid-stage of the disease, characterizing the prodrome and early stages in humans is currently challenging. To overcome these challenges, we use the validated TgF344-AD (F344-Tg(Prp-APP, Prp-PS1)19/Rrrc) transgenic rat model that manifests cognitive, behavioral, and neuropathological dysfunction akin to AD in humans. Objectives: The overarching goal of our work is to test the central hypothesis that pathology and related behavioral deficits such as communication dysfunction in part manifest in the peripheral nervous system and corresponding target tissues already in the early stages. The primary aims of this study are to test the hypotheses that: (1) changes in ultrasonic vocalizations (USV) occur in the prodromal stage at 6 months of age and worsen at 9 months of age, (2) inflammation as well as AD-related pathology can be found in the thyroarytenoid muscle (TA) at 12 months of age (experimental endpoint tissue harvest), and to (3) demonstrate that the TgF344-AD rat model is an appropriate model for preclinical investigations of early AD-related vocal deficits. Methods: USVs were collected from male TgF344-AD (N = 19) and wildtype (WT) Fischer-344 rats (N = 19) at 6 months (N = 38; WT: n = 19; TgF344-AD: n = 19) and 9 months of age (N = 18; WT: n = 10; TgF344-AD: n = 8) and acoustically analyzed for duration, mean power, principal frequency, low frequency, high frequency, peak frequency, and call type. RT-qPCR was used to assay peripheral inflammation and AD-related pathology via gene expressions in the TA muscle of male TgF344-AD rats (n = 6) and WT rats (n = 6) at 12 months of age. Results: This study revealed a significant reduction in mean power of ultrasonic calls from 6 to 9 months of age and increased peak frequency levels over time in TgF344-AD rats compared to WT controls. Additionally, significant downregulation of AD-related genes Uqcrc2, Bace2, Serpina3n, and Igf2, as well as downregulation of pro-inflammatory gene Myd88 was found in the TA muscle of TgF344-AD rats at 12 months of age. Discussion: Our findings demonstrate early and progressive vocal deficits in the TgF344-AD rat model. We further provide evidence of dysregulation of AD-pathology-related genes as well as inflammatory genes in the TA muscles of TgF344-AD rats in the early stage of the disease, confirming this rat model for early-stage investigations of voice deficits and related pathology.

Progressive Protrusive Tongue Exercise Does Not Alter Aging Effects in Retrusive Tongue Muscles.

Purpose: Exercise-based treatment approaches for dysphagia may improve swallow function in part by inducing adaptive changes to muscles involved in swallowing and deglutition. We have previously shown that both aging and progressive resistance tongue exercise, in a rat model, can induce biological changes in the genioglossus (GG); a muscle that elevates and protrudes the tongue. However, the impacts of progressive resistance tongue exercise on the retrusive muscles (styloglossus, SG; hyoglossus, HG) of the tongue are unknown. The purpose of this study was to examine the impact of a progressive resistance tongue exercise regimen on the retrusive tongue musculature in the context of aging. Given that aging alters retrusive tongue muscles to more slowly contracting fiber types, we hypothesized that these biological changes may be mitigated by tongue exercise. Methods: Hyoglossus (HG) and styloglossus (SG) muscles of male Fischer 344/Brown Norway rats were assayed in age groups of young (9 months old, n = 24), middle-aged (24 months old, n = 23), and old (32 months old, n = 26), after receiving an 8-week period of either progressive resistance protrusive tongue exercise, or sham exercise conditions. Following exercise, HG and SG tongue muscle contractile properties were assessed in vivo. HG and SG muscles were then isolated and assayed to determine myosin heavy chain isoform (MyHC) composition. Results: Both retrusive tongue muscle contractile properties and MyHC profiles of the HG and SG muscles were significantly impacted by age, but were not significantly impacted by tongue exercise. Old rats had significantly longer retrusive tongue contraction times and longer decay times than young rats. Additionally, HG and SG muscles showed significant MyHC profile changes with age, in that old groups had slower MyHC profiles as compared to young groups. However, the exercise condition did not induce significant effects in any of the biological outcome measures. Conclusion: In a rat model of protrusive tongue exercise, aging induced significant changes in retrusive tongue muscles, and these age-induced changes were unaffected by the tongue exercise regimen. Collectively, results are compatible with the interpretation that protrusive tongue exercise does not induce changes to retrusive tongue muscle function.

Respiratory-swallow coordination in a rat model of chemoradiation.

BACKGROUND: Chemoradiation treatment (CRT) for head and neck cancer (HNC) is associated with postswallow inhale events that elevate the risk of penetration/aspiration. The purpose of this study was to assess the validity of a rat model for investigating the effect of CRT on respiratory-swallow coordination. METHODS: Videofluoroscopic swallow study was performed on 10 Sprague-Dawley rats 3 months post-CRT (3 mg/kg Cisplatin, 10 fractions of 4.5 Gy/day radiotherapy to tongue base), and 10 naïve controls. We examined the effect of CRT on swallow apnea duration, diaphragm movement, and bolus kinematics. RESULTS: CRT rats had a significant increase in postswallow inhale (p = 0.008), which was associated with significantly longer swallow apnea durations, lower diaphragm displacement at swallow onset, and faster pharyngoesophageal bolus speed. CONCLUSION: The rat CRT model is valid for the study of respiratory-swallow coordination due to the consistency of findings in this study with those reported in clinical CRT studies in HNC.

Central activation deficits contribute to post stroke lingual weakness in a rat model.

Lingual weakness frequently occurs after stroke and is associated with deficits in speaking and swallowing. Chronic weakness after stroke has been attributed to both impaired central activation of target muscles and reduced force-generating capacity within muscles. How these factors contribute to lingual weakness is not known. We hypothesized that lingual weakness due to middle cerebral artery occlusion (MCAO) would manifest as reduced muscle force capacity and reduced muscle activation. Rats were randomized into MCAO or sham surgery groups. Maximum volitional tongue forces were quantified 8 wk after surgery. Hypoglossal nerve stimulation was used to assess maximum stimulated force, muscle twitch properties, and force-frequency response. The central activation ratio was determined by maximum volitional/maximum stimulated force. Genioglossus muscle fiber type properties and neuromuscular junction innervation were assessed. Maximum volitional force and the central activation ratio were significantly reduced with MCAO. Maximum stimulated force was not significantly different. No significant differences were found for muscle twitch properties, unilateral contractile properties, muscle fiber type percentages, or fiber size. However, the twitch/tetanus ratio was significantly increased in the MCAO group relative to sham. A small but significant increase in denervated neuromuscular junctions (NMJs) and fiber-type grouping occurred in the contralesional genioglossus. Results suggest that the primary cause of chronic lingual weakness after stroke is impaired muscle activation rather than a deficit of force-generating capacity in lingual muscles. Increased fiber type grouping and denervated NMJs in the contralesional genioglossus suggest that partial reinnervation of muscle fibers may have preserved force-generating capacity, but not optimal activation patterns.NEW & NOTEWORTHY Despite significant reductions in maximum volitional forces, the intrinsic force-generating capacity of the protrusive lingual muscles was not reduced with unilateral cerebral ischemia. Small yet significant increases in denervated NMJs and fiber-type grouping of the contralesional genioglossus suggest that the muscle underwent denervation and reinnervation. Together these results suggest that spontaneous neuromuscular plasticity was sufficient to prevent atrophy, yet central activation deficits remain and contribute to chronic lingual weakness after stroke.

Effects of inhaled fluticasone propionate on extrinsic tongue muscles in rats.

Obstructive sleep apnea (OSA) is more common in patients with asthma, and inhaled corticosteroids may contribute to OSA pathogenesis in these patients. This study tested the effects of orally inhaled fluticasone propionate (FP) on extrinsic tongue muscles. Unanesthetized rats were treated with FP or placebo for 28 days. On day 29, tongue retrusive and protrusive functions were tested via hypoglossal nerve stimulation under a state of anesthesia, followed by genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscle extraction, after euthanasia, for histology [myosin heavy chain (MHC) fibers and laminin content reflecting extracellular matrix (ECM)]. On protrusive testing, FP increased percent maximum tetanic force at 40 Hz (P = 0.03 vs. placebo) and endurance index (P = 0.029 vs. placebo). On retrusive testing, FP increased maximum twitch (P = 0.026 vs. placebo) and tetanic forces (P = 0.02 vs. placebo) with no effect on endurance index. On histology, FP increased GG cross-sectional area of MHC type IIa (P = 0.036 vs. placebo) and tended to increase type IIb (P = 0.057 vs. placebo) fibers and HG MHC IIx fibers (P = 0.065). The FP group had significantly increased laminin-stained areas, of greatest magnitude in the HG muscle. FP affects tongue protrusive and retrusive functions differently, concurrent with a shift in MHC fibers and increased ECM accumulation. These differential alterations may destabilize the tongue's "muscle hydrostat" during sleep and promote collapse.NEW & NOTEWORTHY The effects of inhaled corticosteroid on upper airway may contribute to OSA pathogenesis in asthma. In this study, we tested the effects of orally inhaled fluticasone propionate on tongue protrusive and retrusive functions and on tongue extrinsic muscle fiber composition and molecular properties. We found that fluticasone treatment: 1) increased protrusive endurance and retrusive maximum twitch and tetanic force; and 2) on histology, increased cross-sectional area of myosin heavy chain (MHC) type IIa fibers and tended to increase cross-sectional area of MHC type IIb fibers in the protrusive muscle and of MHC IIx fibers in the retrusors. It also increased laminin-stained areas, across extrinsic tongue muscles, of greatest magnitude in the retrusors; and 3) reduced protein degradation and activated pathways associated with increased protein synthesis in the protrusor. These differential effects on the protrusors and retrusors may destabilize the tongue's "muscle hydrostat" properties during sleep and promote collapse.

Laryngeal muscle biology in the Pink1-/- rat model of Parkinson disease.

Neuromuscular pathology is found in the larynx and pharynx in humans with Parkinson disease (PD); however, it is unknown when this pathology emerges. We hypothesized that pathology occurs in early (premanifest) stages. To address this, we used the Pink1-/- rat model of PD, which shows age-dependent dopaminergic neuron loss, locomotor deficits, and deficits related to laryngeal function. We report findings in the thyroarytenoid muscle (TA) in Pink1-/- rats compared with wild-type (WT) control rats at 4 and 6 mo of age. TAs were analyzed for force production, myosin heavy chain isoform (MyHC), centrally nucleated myofibers, neural cell adhesion molecule, myofiber size, and muscle section size. Compared with WT, Pink1-/- TA had reductions in force levels at 1-Hz stimulation and 20-Hz stimulation, increases in relative levels of MyHC 2L, increases in incidence of centrally nucleated myofibers in the external division of the TA, and reductions in myofiber size of the vocalis division of the TA at 6 mo of age. Alterations of laryngeal muscle biology occur in a rat model of premanifest PD. Although these alterations are statistically significant, their functional significance remains to be determined. NEW & NOTEWORTHY Pathology of peripheral nerves and muscle has been reported in the larynx and pharynx of humans diagnosed with Parkinson disease (PD); however, it is unknown whether differences of laryngeal muscle occur at premanifest stages. This study examined the thyroarytenoid muscles of the Pink1-/- rat model of PD for differences of muscle biology compared with control rats. Thyroarytenoid muscles of Pink1-/- rats at premanifest stages show differences in multiple measures of muscle biology.

Giving a good start to a new life via maternal brain allostatic adaptations in pregnancy.

Successful pregnancy requires adjustments to multiple maternal homeostatic mechanisms, governed by the maternal brain to support and enable survival of the growing fetus and placenta. Such adjustments fit the concept of allostasis (stability through change) and have a cost: allostatic load. Allostasis is driven by ovarian, anterior pituitary, placental and feto-placental hormones acting on the maternal brain to promote adaptations that support the pregnancy and protect the fetus. Many women carry an existing allostatic load into pregnancy, from socio-economic circumstances, poor mental health and in 'developed' countries, also from obesity. These pregnancies have poorer outcomes indicating negative interactions (failing allostasis) between pre-pregnancy and pregnancy allostatic loads. Use of animal models, such as adult prenatally stressed female offspring with abnormal neuroendocrine, metabolic and behavioural phenotypes, to probe gene expression changes, and epigenetic mechanisms in the maternal brain in adverse pregnancies are discussed, with the prospect of ameliorating poor pregnancy outcomes.

Tongue Force Training Induces Plasticity of the Lingual Motor Cortex in Young Adult and Aged Rats.

Tongue exercise programs are used clinically for dysphagia in aged individuals and have been shown to improve lingual strength. However, the neural mechanisms of age-related decline in swallowing function and its association with lingual strength are not well understood. Using an established rat model of aging and tongue exercise, we hypothesized that the motor cortex of aged rats would have a smaller lingual motor map area than young adult rats and would increase in size as a function of tongue exercise. Over 8 weeks, rats either underwent a progressive resistance tongue exercise program (TE), learned the task but did not exercise (trained controls, TC), or were naïve untrained controls (UC). Cortical motor map areas for tongue and jaw were determined using intracortical microstimulation (ICMS). Rats in the TE and TC groups had a significantly larger motor cortex region for the tongue than the UC group. Lingual cortical motor area was not correlated with protrusive tongue force gains and did not differ significantly with age. These results suggest that learning a novel tongue force skill was sufficient to induce plasticity of the lingual motor cortex yet increasing tongue strength with progressive resistance exercise did not significantly expand the lingual motor area beyond the gains that occurred through the skilled learning component.

The osmoresponsiveness of oxytocin and vasopressin neurones: Mechanisms, allostasis and evolution.

In the rat supraoptic nucleus, every oxytocin cell projects to the posterior pituitary, and is involved both in reflex milk ejection during lactation and in regulating uterine contractions during parturition. All are also osmosensitive, regulating natriuresis. All are also regulated by signals that control appetite, including the neural and hormonal signals that arise from the gut after food intake and from the sites of energy storage. All are also involved in sexual behaviour, anxiety-related behaviours and social behaviours. The challenge is to understand how a single population of neurones can coherently regulate such a diverse set of functions and adapt to changing physiological states. Their multiple functions arise from complex intrinsic properties that confer sensitivity to a wide range of internal and environmental signals. Many of these properties have a distant evolutionary origin in multifunctional, multisensory neurones of Urbilateria, the hypothesised common ancestor of vertebrates, insects and worms. Their properties allow different patterns of oxytocin release into the circulation from their axon terminals in the posterior pituitary into other brain areas from axonal projections, as well as independent release from their dendrites.

Effect of neuromuscular electrical stimulation frequency on muscles of the tongue.

INTRODUCTION: Neuromuscular electrical stimulation (NMES) for the treatment of swallowing disorders is delivered at a variety of stimulation frequencies. We examined the effects of stimulation frequency on tongue muscle plasticity in an aging rat model. METHODS: Eighty-six young, middle-aged, and old rats were assigned to either bilateral hypoglossal nerve stimulation at 10 or 100 Hz (5 days/week, 8 weeks), sham, or no-implantation conditions. Muscle contractile properties and myosin heavy chain (MyHC) composition were determined for hyoglossus (HG) and styloglossus (SG) muscles. RESULTS: Eight weeks of 100-Hz stimulation resulted in the greatest changes in muscle contractile function with significantly longer contraction and half-decay times, the greatest reduction in fatigue, and a transition toward slowly contracting, fatigue-resistant MyHC isoforms. DISCUSSION: NMES at 100-Hz induced considerable changes in contractile and phenotypic profiles of HG and SG muscles, suggesting higher frequency NMES may yield a greater therapeutic effect. Muscle Nerve, 2018.

Pink1 -/- Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology.

Parkinson disease (PD) compromises oropharyngeal swallowing, which negatively affects quality of life and contributes to aspiration pneumonia. Dysphagia often begins early in the disease process, and does not improve with standard therapies. As a result, swallowing deficits are undertreated in the PD population. The Pink1 -/- rat is used to model PD, and demonstrates widespread brainstem neuropathology in combination with early-onset sensorimotor dysfunction; however, to date, swallowing behaviors have not been evaluated. To test the hypothesis that Pink1 -/- rats demonstrate early-onset differences in swallowing, we analyzed within-subject oropharyngeal swallowing using videofluoroscopy. Pink1 -/- and wildtype (WT) controls at 4 (Pink1 -/- n = 16, WT = 16) and 8 (Pink1 -/- n = 12, WT = 12) months of age were tested. The average and maximum bolus size was significantly increased in Pink1 -/- rats at both 4 and 8 months. Bolus average velocity was increased at 8 months for all animals; yet, Pink1 -/- animals had significantly increased velocities compared to WT at 8 months. The data show a significant reduction in mastication rate for Pink1 -/- rats at 8 months suggesting the onset of oromotor dysfunction begins at this time point. Relationships among swallowing variables and neuropathological findings, such as increased alpha-synuclein protein in the nucleus ambiguus and reductions in noradrenergic cells in the locus coeruleus in the Pink1 -/- rats, were determined. The presence of early oropharyngeal swallowing deficits and relationships to brainstem pathology in Pink1-/- rat models of PD indicate that this may be a useful model of early swallowing deficits and their mechanisms. These findings suggest clinical implications for early detection and management of dysphagia in PD.

Fifty Years of Advances in Neuroendocrinology.

Importance of the neuroendocrine brain for health and happiness has become clear since the 1960s. Foundations laid 100 years ago culminated in Geoffrey W Harris's model of control by the brain of secretion of anterior and posterior pituitary gland hormones through, respectively, releasing factors secreted into the hypothalamic-hypophysial portal system, and directly from axon terminals into the systemic circulation. Confirmation, expansion and deepening of knowledge and understanding have followed increasingly sophisticated technology. This allowed chemical characterisation of the posterior pituitary hormones, oxytocin and vasopressin, the releasing factors, their receptors and genes, location of the neurosecretory neurons in the hypothalamus, and how their activity is controlled, including by neural and hormonal feedback, and how hormone rhythms are generated. Wider roles of these neurons and their peptides in the brain are now recognised: in reproductive and social behaviours, emotions and appetite. Plasticity and epigenetic programming of neuroendocrine systems have emerged as important features.

The effects of treadmill running on aging laryngeal muscle structure.

OBJECTIVES/HYPOTHESIS: Age-related changes in laryngeal muscle structure and function may contribute to deficits in voice and swallowing observed in elderly people. We hypothesized that treadmill running, an exercise that increases respiratory drive to upper airway muscles, would induce changes in thyroarytenoid muscle myosin heavy chain (MHC) isoforms that are consistent with a fast-to-slow transformation in muscle fiber type. STUDY DESIGN: Randomized parallel group controlled trial. METHODS: Fifteen young adult and 14 old Fischer 344/Brown Norway rats received either treadmill running or no exercise (5 days/week/8 weeks). Myosin heavy chain isoform composition in the thyroarytenoid muscle was examined at the end of 8 weeks. RESULTS: Significant age and treatment effects were found. The young adult group had the greatest proportion of superfast-contracting MHCIIL isoform. The treadmill running group had the lowest proportion of MHCIIL and the greatest proportion of MHCIIx isoforms. CONCLUSION: Thyroarytenoid muscle structure was affected both by age and treadmill running in a fast-to-slow transition that is characteristic of exercise manipulations in other skeletal muscles. LEVEL OF EVIDENCE: NA. Laryngoscope, 126:672-677, 2016.

mTOR Pathway - Novel Modulator of Astrocyte Activity.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide-3-kinase-related family and has a crucial role in the integration of growth factors, energy factors and nutrient signaling. Abnormal activity of mTOR kinase can cause many neuropathologies, including brain tumours and neurodegenerative diseases. The study confirms that the use of a kinase inhibitor - rapamycin, allows to limit proliferation including inhibition of tumor cells and immune responses. The review presents current knowledge about the role of mTOR in the modulation of nervous system activity focusing on astrocytes which are involved in the maintenance of nervous system homeostasis and support neuronal function. Astroglial activity is associated with the pathogenesis of neurodegenerative diseases like Alzheimer's disease (AD) or Parkinson's disease (PD). Effect of mTOR and its inhibitor on central nervous system functions, in particular astrocytes, is still not fully undersood.

Effects of aging on evoked retrusive tongue actions.

OBJECTIVE: Tongue strength, timing, and coordination deficits may underlie age-related swallowing function. Retrusive tongue actions are likely important in retrograde bolus transport. However, age-related changes in retrusive tongue muscle contractile properties have not been identified in animal studies. Because previous studies employed whole hypoglossal nerve stimulation that activated both protrusive and retrusive tongue muscles, co-contraction may have masked retrusive muscle force decrements. The hypotheses of this study were: (1) retrusive tongue muscle contraction forces would be diminished and temporal characteristics prolonged in old rats when lateral nerves were selectively activated, and (2) greater muscle contractile forces with selective lateral branch stimulation would be found relative to whole hypoglossal nerve stimulation. DESIGN: Nineteen Fischer 344/Brown Norway rats (9 old, 10 young adult) underwent tongue muscle contractile property recording elicited by: (1) bilateral whole hypoglossal nerve stimulation, and (2) selective lateral branch stimulation. Twitch contraction time (CT), half-decay time, maximal twitch and tetanic forces, and a fatigue index were measured. RESULTS: For whole nerve stimulation, CT was significantly longer in the old group. No significant age group differences were found with selective lateral nerve stimulation. Significantly reduced twitch forces (old group only), increased tetanic forces and significantly less fatigue were found with selective lateral nerve stimulation than with whole hypoglossal stimulation. CONCLUSIONS: Retrusive tongue forces are not impaired in old rats. Deficits observed in swallowing with aging may be due to other factors such as inadequate bolus propulsive forces, mediated by protrusive tongue muscles, or timing/coordination of muscle actions.

5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats.

Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1ß; IL-1ß) in adulthood, compared with controls. IL-1ß acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3ß-androstanediol (3ß-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1ß (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3ß-diol normalized HPA axis responses to IL-1ß in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1ß. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.

Effects of age and radiation treatment on function of extrinsic tongue muscles.

BACKGROUND: Radiation treatment for head and neck cancer often results in difficulty swallowing. Muscle weakness and fibrosis have been identified clinically as possible etiologies for swallowing problems following radiation. Aging may compound the effects of radiation on swallowing because radiation-induced damage to muscles and other tissues critical for the oropharyngeal swallow is overlaid on a declining sensorimotor system. However, there have been no investigations of the manner in which aging and radiation treatment effects combine to impact tongue muscles, which are critical effectors of the oropharyngeal swallow. METHODS: Thirty-seven male Fisher 344/Brown Norway rats were divided into four groups; young adults (9 month old), old (32 months old), young radiation (9 months), and old radiation (32 months old). Two fractions of 11 Gy on consecutive days was delivered by external beam radiation to the ventral side of the rat's body over the anterior portion (20 X 30 mm area) of the anterior digastric muscle. Two-way analysis of variance (ANOVA) was used to examine the effects of age and radiation and their interaction on muscle contractile properties. Post-hoc testing was completed using Fisher's least significant differences (LSD). RESULTS: Radiation was associated with a significant decrease in tongue force production and reduced speed of tongue muscle contraction. However, radiation treatment did not lead to muscle atrophy and fibrosis formation in the GG muscle. Radiation treatment did not exacerbate atrophic changes observed with aging, or lead to additional fibrosis formation in the GG muscle from that observed in the other groups. CONCLUSIONS: The purpose of this research was to determine the effect of radiation on muscles of the tongue and to determine whether aging altered the extent of radiation injury to tongue muscles. Radiation was associated with a significant decrease in tongue force production and reduced speed of tongue muscle contraction, and the reduction in the speed of tongue muscle contraction was exacerbated in the aged-rat tongue. This work provides a foundation for future investigations of treatments for concurrent effects of aging and radiation on muscles of the tongue and swallowing.