Lateralization of acoustic signals by dichotically listening budgerigars (Melopsittacus undulatus).

Sound localization allows humans and animals to determine the direction of objects to seek or avoid and indicates the appropriate position to direct visual attention. Interaural time differences (ITDs) and interaural level differences (ILDs) are two primary cues that humans use to localize or lateralize sound sources. There is limited information about behavioral cue sensitivity in animals, especially animals with poor sound localization acuity and small heads, like budgerigars. ITD and ILD thresholds were measured behaviorally in dichotically listening budgerigars equipped with headphones in an identification task. Budgerigars were less sensitive than humans and cats, and more similar to rabbits, barn owls, and monkeys, in their abilities to lateralize dichotic signals. Threshold ITDs were relatively constant for pure tones below 4 kHz, and were immeasurable at higher frequencies. Threshold ILDs were relatively constant over a wide range of frequencies, similar to humans. Thresholds in both experiments were best for broadband noise stimuli. These lateralization results are generally consistent with the free field localization abilities of these birds, and add support to the idea that budgerigars may be able to enhance their cues to directional hearing (e.g., via connected interaural pathways) beyond what would be expected based on head size.

Identification of auditory distance cues by zebra finches (Taeniopygia guttata) and budgerigars (Melopsittacus undulatus).

The present study examined auditory distance perception cues in a non-territorial songbird, the zebra finch (Taeniopygia guttata), and in a non-songbird, the budgerigar (Melopsittacus undulatus). Using operant conditioning procedures, three zebra finches and three budgerigars were trained to identify 1- (Near) and 75-m (Far) recordings of three budgerigar contact calls, one male zebra finch song, and one female zebra finch call. Once the birds were trained on these endpoint stimuli, other stimuli were introduced into the operant task. These stimuli included recordings at intermediate distances and artificially altered stimuli simulating changes in overall amplitude, high-frequency attenuation, reverberation, and all three cues combined. By examining distance cues (amplitude, high-frequency attenuation, and reverberation) separately, this study sought to determine which cue was the most salient for the birds. The results suggest that both species could scale the stimuli on a continuum from Near to Far and that amplitude was the most important cue for these birds in auditory distance perception, as in humans and other animals.

Effects of syllable-final segment duration on the identification of synthetic speech continua by birds and humans.

In an attempt to test whether experience with or knowledge of language is necessary to show typical speaking rate effects in the perception of speech, budgerigars (Melopsittacus undulatus) and humans categorized stimuli from the synthetic continua /ba/-/wa/ and /bas/-/was/, with both short and long syllable-final phonemes. This comparative approach aims to shed some light on whether knowledge of language has a role in rate normalization effects, such as using duration information as an indicator of speaking rate in human speech perception. Syllable-final phoneme durations were varied, and were either temporally adjacent to the initial target (CV series) or were nonadjacent (CVC series). The birds were always influenced by syllable-final duration variation in the present experiments and displayed greater boundary shifts than humans. In humans, there was a significant boundary shift observed in the CV series, but there were no effects of duration variation in the final segment in the CVC series. The results from the birds suggest that specialized speech-based principles may not be necessary for explaining findings of grouping speech or speechlike elements in perception.

The Franssen effect illusion in budgerigars (Melopsittacus undulatus) and zebra finches (Taeniopygia guttata).

The properties of the Franssen effect (FE) were measured in budgerigars and zebra finches. To elicit the FE, listeners are presented with a signal which has been split into a transient component, carrying an abrupt onset and ramped offset and separated in space from the sustained component which has a slowly rising onset and longer duration. When these two signals are played under certain conditions, the perception is that of a long-duration steady state tone being played at the location of the transient. The birds were trained using operant conditioning methods on a categorization task to peck a left key when presented with a stimulus from a left speaker and to peck a right key when presented with a stimulus from a right speaker. Once training was completed, FE stimuli were presented during a small proportion of trials. The FE was measured at speaker separations of 60 degrees and 180 degrees in both echoic and echoic-reduced conditions. Both species of birds exhibited the FE, although to varying degrees, across conditions. These results show that nonmammals also experience the FE illusion in confusing listening situations in a manner similar to mammals, suggestive of similar auditory processing mechanisms.

Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice.

Transgenic sickle mice expressing betaS hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-kappaB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NF-kappaB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-kappaB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice.

Polynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice.

Individuals with sickle-cell disease (SCD) and transgenic sickle mice expressing human betaS globin exhibit enhanced reactive oxygen species (ROS) production, vascular inflammation, and episodic vasoocclusion. We hypothesize that reduction of ROS will reduce endothelial-cell activation and adhesion-molecule expression, thereby inhibiting vasoocclusion. To test this hypothesis, we measured endothelial-cell activation, adhesion-molecule expression, and vasoocclusion in sickle mice after administering i.v. polynitroxyl albumin (PNA), a superoxide dismutase and catalase mimetic. Untreated sickle mice, compared with normal mice, showed increased activation of nuclear factor-kappaB (NF-kappaB), an oxidant-sensitive transcription factor, in their lungs, livers, and skin. NF-kappaB activation was increased further in the livers and skin of sickle but not normal mice after hypoxia-reoxygenation. IV administration of PNA inhibited NF-kappaB activation by 60% (P < .01) in the lungs and by 33% (P < .05) in the livers of sickle mice after hypoxia-reoxygenation. PNA also reduced the expression of vascular cell-adhesion molecule-1 (VCAM-1) by 57% in lung (P < .05) and by 33% in liver (P < .05) and reduced the expression of intercellular-adhesion molecule-1 (ICAM-1) by 40% in lung (P < .05) and by 53% in liver (P < .05). PNA inhibited a hypoxia-reoxygenation-induced increase in leukocyte rolling (P < .01) and adhesion (P < .05) in venules of the dorsal skin. Most importantly, PNA completely inhibited hypoxia-reoxygenation-induced vasoocclusion (P < .001). Control albumin had no effect on NF-kappaB, VCAM-1, ICAM-1, rolling, adhesion, or vasoocclusion. We speculate that therapies to reduce oxidative stress will inhibit inflammation and vasoocclusion in SCD.

Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice.

Activation of vascular endothelium plays an essential role in vasoocclusion in sickle cell disease. The anti-inflammatory agents dexamethasone and adhesion molecule-blocking antibodies were used to inhibit endothelial cell activation and hypoxia-induced vasoocclusion. Transgenic sickle mice, expressing human alpha-, beta(S)-, and beta(S-Antilles)-globins, had an activated vascular endothelium in their liver, lungs, and skin, as exhibited by increased activation of NF-kappaB compared with normal mice. NF-kappaB activation increased further in the liver and skin after sickle mice were exposed to hypoxia. Sickle mice had decreases in red blood cell (RBC) velocities and developed vasoocclusions in subcutaneous venules in response to hypoxia. Dexamethasone pretreatment prevented decreases in RBC velocities and inhibited vasoocclusions and leukocyte-endothelium interactions in venules after hypoxia. Dexamethasone treatment inhibited NF-kappaB, VCAM-1, and ICAM-1 expression in the liver, lungs, and skin of sickle mice after hypoxia-reoxygenation. VCAM-1 or ICAM-1 blockade with monoclonal antibodies mimicked dexamethasone by inhibiting vasoocclusion and leukocyte adhesion in sickle mice, demonstrating that endothelial cell activation and VCAM-1 and ICAM-1 expression are necessary for hypoxia-induced vasoocclusion in sickle mice. VCAM-1, ICAM-1, and vasoocclusion increased significantly 3 days after dexamethasone discontinuation, possibly explaining rebounds in vasoocclusive crises observed after withdrawal of glucocorticosteroids in sickle patients. We conclude that anti-inflammatory treatments that inhibit endothelial cell activation and adhesion molecule expression can inhibit vasoocclusion in sickle cell disease. Rebounds in vasoocclusive crises after dexamethasone withdrawal are caused by rebounds in endothelial cell activation.

Microvascular blood flow and stasis in transgenic sickle mice: utility of a dorsal skin fold chamber for intravital microscopy.

Vascular inflammation, secondary to ischemia-reperfusion injury, may play an essential role in vaso-occlusion in sickle cell disease (SCD). To investigate this hypothesis, dorsal skin fold chambers (DSFCs) were implanted on normal and transgenic sickle mice expressing human alpha and beta(s)/beta(s-Antilles) globin chains. Microvessels in the DSFC were visualized by intravital microscopy at baseline in ambient air and after exposure to hypoxia-reoxygenation. The mean venule diameter decreased 9% (P < 0.01) in sickle mice after hypoxia-reoxygenation but remained constant in normal mice. The mean RBC velocity and wall shear rate decreased 55% (P < 0.001) in sickle but not normal mice after hypoxia-reoxygenation. None of the venules in normal mice became static at any time during hypoxia-reoxygenation; however, after 1 hr of hypoxia and 1 hr of reoxygenation, 11.9% of the venules in sickle mice became static (P < 0.001). After 1 hr of hypoxia and 4 hr of reoxygenation, most of the stasis had resolved; only 3.6% of the subcutaneous venules in sickle mice remained static (P = 0.01). All of the venules were flowing again after 24 hr of reoxygenation. Vascular stasis could not be induced in the subcutaneous venules of sickle mice by tumor necrosis factor alpha (TNF-alpha). Leukocyte rolling flux and firm adhesion, manifestations of vascular inflammation, were significantly higher at baseline in sickle mice compared to normal (P < 0.01) and increased 3-fold in sickle (P < 0.01), but not in normal mice, after hypoxia-reoxygenation. Plugs of adherent leukocytes were seen at bifurcations at the beginning of static venules. Misshapen RBCs were also seen in subcutaneous venules.