Tracy L. Baker-Herman
University of Wisconsin-Madison
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Featured researches published by Tracy L. Baker-Herman.
Nature Neuroscience | 2004
Tracy L. Baker-Herman; David D. Fuller; Ryan W. Bavis; A. G. Zabka; Francis J. Golder; Nicholas J Doperalski; Rebecca A. Johnson; Jyoti J. Watters; Gordon S. Mitchell
Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo.
The Journal of Neuroscience | 2002
Tracy L. Baker-Herman; Gordon S. Mitchell
Respiratory long-term facilitation (LTF) is a form of serotonin-dependent plasticity induced by intermittent hypoxia. LTF is manifested as a long-lasting increase in respiratory amplitude (and frequency) after the hypoxic episodes have ended. We tested the hypotheses that LTF of phrenic amplitude requires spinal serotonin receptor activation and spinal protein synthesis. A broad-spectrum serotonin receptor antagonist (methysergide) or protein synthesis inhibitors (emetine or cycloheximide) were injected intrathecally in the cervical spinal cord of anesthetized rats. Control rats, injected with vehicle (artificial CSF), exhibited an augmented phrenic burst amplitude after three 5 min episodes of hypoxia (78 ± 15% above baseline, 60 min after hypoxia; p < 0.05), indicating LTF. Pretreatment with methysergide, emetine, or cycloheximide attenuated or abolished phrenic LTF (20 ± 4, 0.2 ± 11, and 20 ± 2%, respectively; allp > 0.05). With protein synthesis inhibitors, phrenic LTF differed from control by 15 min after intermittent hypoxia. As an internal control against unintended drug distribution, we measured respiratory LTF in hypoglossal (XII) motor output. At 60 min after intermittent hypoxia, all treatment groups exhibited similar XII LTF (artificial CSF, 44 ± 10%; methysergide, 40 ± 5%; emetine, 35 ± 9%; and cycloheximide, 57 ± 29%; allp < 0.05), suggesting that drugs were restricted at effective doses to the spinal cord. We conclude that phrenic LTF requires spinal serotonin receptor activation and protein synthesis. Serotonin receptors on phrenic motoneuron dendrites may induce new protein synthesis, thereby giving rise to phrenic LTF.
The Journal of Neuroscience | 2008
Francis J. Golder; Lavanya Ranganathan; Irawan Satriotomo; Michael S. Hoffman; Mary Rachael Lovett-Barr; Jyoti J. Watters; Tracy L. Baker-Herman; Gordon S. Mitchell
Acute intermittent hypoxia elicits a form of spinal, brain-derived neurotrophic factor (BDNF)-dependent respiratory plasticity known as phrenic long-term facilitation. Ligands that activate Gs-protein-coupled receptors, such as the adenosine 2a receptor, mimic the effects of neurotrophins in vitro by transactivating their high-affinity receptor tyrosine kinases, the Trk receptors. Thus, we hypothesized that A2a receptor agonists would elicit phrenic long-term facilitation by mimicking the effects of BDNF on TrkB receptors. Here we demonstrate that spinal A2a receptor agonists transactivate TrkB receptors in the rat cervical spinal cord near phrenic motoneurons, thus inducing long-lasting (hours) phrenic motor facilitation. A2a receptor activation increased phosphorylation and new synthesis of an immature TrkB protein, induced TrkB signaling through Akt, and strengthened synaptic pathways to phrenic motoneurons. RNA interference targeting TrkB mRNA demonstrated that new TrkB protein synthesis is necessary for A2a-induced phrenic motor facilitation. A2a receptor activation also increased breathing in unanesthetized rats, and improved breathing in rats with cervical spinal injuries. Thus, small, highly permeable drugs (such as adenosine receptor agonists) that transactivate TrkB receptors may provide an effective therapeutic strategy in the treatment of patients with ventilatory control disorders, such as obstructive sleep apnea, or respiratory insufficiency after spinal injury or during neurodegenerative diseases.
Respiratory Physiology & Neurobiology | 2008
Tracy L. Baker-Herman; Gordon S. Mitchell
Acute intermittent (AIH), but not acute sustained hypoxia (ASH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). In anesthetized rats, LTF is expressed as increased respiratory-related nerve burst amplitude, with variable effects on burst frequency. We analyzed a large data set from multiple investigators using the same experimental protocol to determine factors influencing frequency LTF. Our meta-analysis revealed that AIH elicits both phrenic amplitude and frequency LTF in anesthetized and vagotomized rats, but frequency LTF is small in comparison with amplitude LTF (12% versus 60%, respectively). ASH elicits a small, but significant frequency and amplitude LTF (8% and 10%, respectively) that is not significantly different than controls. Similar to all published reports, analysis of this large data set confirms that phrenic amplitude LTF following AIH is significantly greater than ASH. Multiple regression analysis revealed a strong correlation between baseline burst frequency and frequency LTF. Variations in baseline burst frequency may contribute to variation in frequency LTF and may underlie the apparent effects of some drug treatments.
The Journal of Neuroscience | 2008
Julia E. R. Wilkerson; Irawan Satriotomo; Tracy L. Baker-Herman; Jyoti J. Watters; Gordon S. Mitchell
Phrenic long-term facilitation (pLTF) is a serotonin-dependent form of pattern-sensitive respiratory plasticity induced by intermittent hypoxia (IH), but not sustained hypoxia (SH). The mechanism(s) underlying pLTF pattern sensitivity are unknown. SH and IH may differentially regulate serine/threonine protein phosphatase activity, thereby inhibiting relevant protein phosphatases uniquely during IH and conferring pattern sensitivity to pLTF. We hypothesized that spinal protein phosphatase inhibition would relieve this braking action of protein phosphatases, thereby revealing pLTF after SH. Anesthetized rats received intrathecal (C4) okadaic acid (25 nm) before SH (25 min, 11% O2). Unlike (vehicle) control rats, SH induced a significant pLTF in okadaic acid-treated rats that was indistinguishable from rats exposed to IH (three 5 min episodes, 11% O2). IH and SH with okadaic acid may elicit pLTF by similar, serotonin-dependent mechanisms, because intravenous methysergide blocks pLTF in rats receiving IH or okadaic acid plus SH. Okadaic acid did not alter IH-induced pLTF. In summary, pattern sensitivity in pLTF may reflect differential regulation of okadaic acid-sensitive serine/threonine phosphatases; presumably, these phosphatases are less active during/after IH versus SH. The specific okadaic acid-sensitive phosphatase(s) constraining pLTF and their spatiotemporal dynamics during and/or after IH and SH remain to be determined.
Respiratory Physiology & Neurobiology | 2010
Tracy L. Baker-Herman; Ryan W. Bavis; J.M. Dahlberg; A.Z. Mitchell; Julia E. R. Wilkerson; Francis J. Golder; P.M. MacFarlane; Jyoti J. Watters; Mary Behan; Gordon S. Mitchell
We tested the hypotheses that: (1) long-term facilitation (LTF) following acute intermittent hypoxia (AIH) varies among three inbred rat strains: Fischer 344 (F344), Brown Norway (BN) and Lewis rats and (2) ventral cervical spinal levels of genes important for phrenic LTF (pLTF) vary in association with pLTF magnitude. Lewis and F344, but not BN rats exhibited significant increases in phrenic and hypoglossal burst amplitude 60min post-AIH that were significantly greater than control experiments without AIH, indicating strain differences in phrenic (98%, 56% and 20%, respectively) and hypoglossal LTF (66%, 77% and 5%, respectively). Ventral spinal 5-HT(2A) receptor mRNA and protein levels were higher in F344 and Lewis versus BN, suggesting that higher 5-HT(2A) receptor levels are associated with greater pLTF. More complex relationships were found for 5-HT(7), BDNF and TrkB mRNA. BN had higher 5-HT(7) and TrkB mRNA versus F344; BN and Lewis had higher BDNF mRNA levels versus F344. Genetic variations in serotonergic function may underlie strain differences in AIH-induced pLTF.
Respiratory Physiology & Neurobiology | 2011
Safraaz Mahamed; Kristi A. Strey; Gordon S. Mitchell; Tracy L. Baker-Herman
We hypothesized that reduced respiratory neural activity elicits compensatory mechanisms of plasticity that enhance respiratory motor output. In urethane-anesthetized and ventilated rats, we reversibly reduced respiratory neural activity for 25-30 min using: hypocapnia (end tidal CO(2)=30 mmHg), isoflurane (~1%) or high frequency ventilation (HFV; ~100 breaths/min). In all cases, increased phrenic burst amplitude was observed following restoration of respiratory neural activity (hypocapnia: 92±22%; isoflurane: 65±22%; HFV: 54±13% baseline), which was significantly greater than time controls receiving the same surgery, but no interruptions in respiratory neural activity (3±5% baseline, p<0.05). Hypocapnia also elicited transient increases in respiratory burst frequency (9±2 versus 1±1bursts/min, p<0.05). Our results suggest that reduced respiratory neural activity elicits a unique form of plasticity in respiratory motor control which we refer to as inactivity-induced phrenic motor facilitation (iPMF). iPMF may prevent catastrophic decreases in respiratory motor output during ventilatory control disorders associated with abnormal respiratory activity.
Veterinary Anaesthesia and Analgesia | 2011
Carrie A. Schroeder; Lindsey B. C. Snyder; Caitlin C Tearney; Tracy L. Baker-Herman; Kristopher M. Schroeder
OBJECTIVE To describe the ultrasound-guided technique to the transversus abdominis plane (TAP) block in the dog and evaluate the spread of a local anesthetic/methylene blue solution. STUDY DESIGN Prospective experimental trial. ANIMALS Ten adult Beagle cadavers weighing 11.1 ± 1.1 kg (mean ± SD). METHODS Transversus abdominis plane (TAP) blocks were performed bilaterally by a single trained individual on unpreserved cadaver dogs using 10 mL of methylene blue/bupivacaine solution per site. Dissection of the abdominal wall was performed within 15-55 minutes of block to determine distribution of injectate and nerve involvement in the transversus abdominis fascial plane. RESULTS The transversus abdominis fascial plane was adequately visualized via ultrasound and injected in twenty hemi-abdominal walls. Segmental branches of T11, T12, T13, L1, L2, and L3 were adequately stained in 20%, 60%, 100%, 100%, 90%, and 30% of injections, respectively. CONCLUSIONS AND CLINICAL RELEVANCE This anatomical study suggests that the transversus abdominis plane (TAP) block would provide adequate regional anesthesia of the abdomen, potentially extending to the cranial and caudal limits of the abdomen. This supports the clinical potential of this block in veterinary medicine.
The Journal of Neuroscience | 2012
Kristi A. Strey; Nicole L. Nichols; Nathan A. Baertsch; Oleg Broytman; Tracy L. Baker-Herman
The neural network controlling breathing must establish rhythmic motor output at a level adequate to sustain life. Reduced respiratory neural activity elicits a novel form of plasticity in circuits driving the diaphragm known as inactivity-induced phrenic motor facilitation (iPMF), a rebound increase in phrenic inspiratory output observed once respiratory neural drive is restored. The mechanisms underlying iPMF are unknown. Here, we demonstrate in anesthetized rats that spinal mechanisms give rise to iPMF and that iPMF consists of at least two mechanistically distinct phases: (1) an early, labile phase that requires atypical PKC (PKCζ and/or PKCι/λ) activity to transition to a (2) late, stable phase. Early (but not late) iPMF is associated with increased interactions between PKCζ/ι and the scaffolding protein ZIP (PKCζ-interacting protein)/p62 in spinal regions associated with the phrenic motor pool. Although PKCζ/ι activity is necessary for iPMF, spinal atypical PKC activity is not necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia, an activity-independent form of spinal respiratory plasticity. Thus, while iPMF and pLTF both manifest as prolonged increases in phrenic burst amplitude, they arise from distinct spinal cellular pathways. Our data are consistent with the hypotheses that (1) local mechanisms sense and respond to reduced respiratory-related activity in the phrenic motor pool and (2) inactivity-induced increases in phrenic inspiratory output require local PKCζ/ι activity to stabilize into a long-lasting iPMF. Although the physiological role of iPMF is unknown, we suspect that iPMF represents a compensatory mechanism, assuring adequate motor output in a physiological system in which prolonged inactivity ends life.
Respiratory Physiology & Neurobiology | 2013
Kristi A. Strey; Nathan A. Baertsch; Tracy L. Baker-Herman
Multiple forms of plasticity are activated following reduced respiratory neural activity. For example, in ventilated rats, a central neural apnea elicits a rebound increase in phrenic and hypoglossal burst amplitude upon resumption of respiratory neural activity, forms of plasticity called inactivity-induced phrenic and hypoglossal motor facilitation (iPMF and iHMF), respectively. Here, we provide a conceptual framework for plasticity following reduced respiratory neural activity to guide future investigations. We review mechanisms giving rise to iPMF and iHMF, present new data suggesting that inactivity-induced plasticity is observed in inspiratory intercostals (iIMF) and point out gaps in our knowledge. We then survey conditions relevant to human health characterized by reduced respiratory neural activity and discuss evidence that inactivity-induced plasticity is elicited during these conditions. Understanding the physiological impact and circumstances in which inactivity-induced respiratory plasticity is elicited may yield novel insights into the treatment of disorders characterized by reductions in respiratory neural activity.