Biomedical subjects

R Mooney

Publications and source records attributed to R Mooney.

At least 19 recordsLinked to original sources

PubMed2005

Physiology of neuronal subtypes in the respiratory-vocal integration nucleus retroamigualis of the male zebra finch.

Learned vocalizations, such as bird song, require intricate coordination of vocal and respiratory muscles. Although the neural basis for this coordination remains poorly understood, it likely includes direct synaptic interactions between respiratory premotor neurons and vocal motor neurons. In birds, as in mammals, the medullary nucleus retroambigualis (RAm) receives synaptic input from higher level respiratory and vocal control centers and projects to a variety of targets. In birds, these include vocal motor neurons in the tracheosyringeal part of the hypoglossal motor nucleus (XIIts), other respiratory premotor neurons, and expiratory motor neurons in the spinal cord. Although various cell types in RAm are distinct in their anatomical projections, their electrophysiological properties remain unknown. Furthermore, although prior studies have shown that RAm provides both excitatory and inhibitory input onto XIIts motor neurons, the identity of the cells in RAm providing either of these inputs remains to be established. To characterize the different RAm neuron types electrophysiologically, we used intracellular recordings in a zebra finch brain stem slice preparation. Based on numerous differences in intrinsic electrophysiological properties and a principal components analysis, we identified two distinct RAm neuron types (types I and II). Antidromic stimulation methods and intracellular staining revealed that type II neurons, but not type I neurons, provide bilateral synaptic input to XIIts. Paired intracellular recordings in RAm and XIIts further indicated that type II neurons with a hyperpolarization-dependent bursting phenotype are a potential source of inhibitory input to XIIts motor neurons. These results indicate that electrically distinct cell types exist in RAm, affording physiological heterogeneity that may play an important role in respiratory-vocal signaling.

Action Potentials↗

PubMed2004

Synaptic transformations underlying highly selective auditory representations of learned birdsong.

Stimulus-specific neuronal responses are a striking characteristic of several sensory systems, although the synaptic mechanisms underlying their generation are not well understood. The songbird nucleus HVC (used here as a proper name) contains projection neurons (PNs) that fire temporally sparse bursts of action potentials to playback of the bird's own song (BOS) but are essentially silent when presented with other acoustical stimuli. To understand how such remarkable stimulus specificity emerges, it is necessary to compare the auditory-evoked responsiveness of the afferents of HVC with synaptic responses in identified HVC neurons. We found that inactivating the interfacial nucleus of the nidopallium (NIf) could eliminate all auditory-evoked subthreshold activity in both HVC PN types, consistent with NIf serving as the major auditory afferent of HVC. Simultaneous multiunit extracellular recordings in NIf and intracellular recordings in HVC revealed that NIf population activity and HVC subthreshold responses were similar in their selectivity for BOS and that NIf spikes preceded depolarizations in all HVC cell types. These results indicate that information about the BOS as well as other auditory stimuli is transmitted synaptically from NIf to HVC. Unlike HVC PNs, however, HVC-projecting NIf neurons fire throughout playback of BOS as well as non-BOS stimuli. Therefore, temporally sparse BOS-evoked firing and enhanced BOS selectivity, manifested as an absence of suprathreshold responsiveness to non-BOS stimuli, emerge in HVC. The transformation to a sparse auditory representation parallels differences in NIf and HVC activity patterns seen during singing, which may point to a common mechanism for encoding sensory and motor representations of song.

Animals↗

PubMed2003

Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionising radiation and chemotherapy toxicity.

l-Deprenyl (R-(-)-deprenyl, selegiline) is an inhibitor of monoamine oxidase-B (MAO-B) that is known to protect nerve cells from a variety of chemical and physical insults. As apoptosis is a common mechanism of radiation-induced cell death, the effect of l-deprenyl on the survival of cultured cells and tissue explants was studied following exposure to gamma radiation. The results obtained were compared with the effects of the less-selective MAO-B inhibitor pargyline and the MAO-A inhibitor clorgyline. l-Deprenyl at a concentration of 10(-9) M protected the nontumorigenic cell line (HaCaT) and normal human urothelial explants from the effects of cobalt-60 gamma radiation, but did not protect tumorigenic human cell lines HaCaT-ras, HPV-transfected human keratinocytes (HPV-G cells), or PC3. Human bladder carcinoma explants were not protected. Clorgyline showed a smaller protective effect of normal cells, whereas pargyline had no effect. Radiation-induced delayed effects (genomic instability measured as delayed cell death) were prevented in normal cells by l-deprenyl but, interestingly, deprenyl appeared to increase the amount of delayed death in the tumorigenic cell lines. Studies using l-deprenyl prior to the exposure of nonmalignant cells to cisplatin showed that cell death due to this agent was also reduced. Treatment of cultures of nontumorigenic cells with l-deprenyl or clorgyline significantly increased the levels of the protein Bcl-2 following irradiation, but there was no such effect on the already-elevated levels of this protein in the tumour samples. Since the Bcl-2 has been shown to be an inhibitor of apoptosis or programmed cell death, this would imply that the protective effects of l-deprenyl and clorgyline involve activation of antiapoptotic pathways within the normal cell. This hypothesis is supported by data showing reduced levels of apoptosis in HaCAT cells and in normal bladder explant cultures following treatment with l-deprenyl.

Animals↗

PubMed2002

A bird's eye view: top down intracellular analyses of auditory selectivity for learned vocalizations.

The "song system" refers to a group of interconnected brain nuclei necessary for the utterance of learned song and for the generation of vocal plasticity important to both song learning and adult song maintenance. Although song learning and, in some species, song maintenance depend on auditory feedback, how audition influences vocalization remains unknown. One attractive idea is that auditory signals propagate directly to those telencephalic nuclei implicated in song patterning, providing a convenient substrate for sensorimotor integration. Consistent with this idea, auditory neurons highly selective for the bird's own song have been detected in telencephalic song nuclei, and lesions of these structures can impair song perception as well as song production. This review discusses evidence for an auditory-perceptual role of the song system, the anatomical pathways by which auditory information enters the song system, the synaptic events underlying highly selective action potential responses to learned song, and the possible roles such activity could play in song learning and maintenance.

Acoustic Stimulation↗

PubMed2001

Auditory representation of the vocal repertoire in a songbird with multiple song types.

Neural mechanisms for representing complex communication sounds must solve the problem of encoding multiple and potentially overlapping signals. Birdsong provides an excellent model for such processing, in that many songbird species produce multiple song types. Although auditory song representations in single song type species have been studied, how song is represented in the brains of species that sing multiple song types remains unknown. Here we examine song type representations in swamp sparrows (Melospiza georgiana), a multiple song type species, by making in vivo intracellular recordings from the telencephalic nucleus HVc, the major auditory-vocal interface in the songbird brain. These recordings show that single HVc relay neurons often generate action potentials to playback of only a single song type, even though synaptic inputs on these cells can be activated by playback of other song types in the bird's repertoire and songs of other birds. These subthreshold response patterns suggest that the song evoked action potential discharge of a single relay neuron is more selective than its presynaptic network. One component of this presynaptic network is likely to be in HVc, because multiple recordings from single birds show that different relay neurons can respond best to different song types, whereas single interneurons can generate action potentials to all song types in the bird's repertoire. These results show that single HVc neurons can generate song type-specific action potential responses, a feature that may facilitate the selective auditory encoding of multiple learned vocalizations in a single brain area.

Action Potentials↗

PubMed2001

Androgens and isolation from adult tutors differentially affect the development of songbird neurons critical to vocal plasticity.

Song learning in oscine birds occurs during a juvenile sensitive period. One idea is that this sensitive period is regulated by changes in the electrophysiological properties of neurons in the telencephalic song nucleus lateral magnocellular nucleus of the anterior neostriatum (LMAN), a structure critical for song development but not adult singing. A corollary of this idea is that manipulations affecting the pace and quality of song learning will concomitantly affect the development of LMAN's electrophysiological properties. Manipulations known to affect song development include treating juvenile male zebra finches with exogenous androgens, which results in abnormally truncated adult songs, and isolation of the juvenile from adult tutors and their songs, which extends the sensitive period for song learning. Previously, we showed that synaptic transmission in LMAN changes over normal song development and that these changes are accelerated or retarded, respectively, by androgen treatment and isolation from an adult tutor. The intrinsic properties of LMAN neurons afford another potential target for regulation by steroid hormones and experience of adult tutors. Indeed previous studies showed that the capacity for LMAN neurons to fire action potentials in bursts, due to a low-threshold calcium spike, and the width of single action potentials in LMAN, wane over development. Here we analyzed these and other intrinsic electrophysiological features of LMAN neurons over normal development, then tested whether either early androgen treatment or isolating juveniles from adult tutors affected the timing of these changes. The present study shows that androgen but not isolation treatment alters the developmental time at which LMAN neurons progress from the bursting to nonbursting phenotype. In addition, other intrinsic properties, including the half-height spike width and the magnitude of the spike afterhyperpolarization (AHP), were found to change markedly over development but only changes to the AHP were androgen sensitive. Interestingly of all of the synaptic and intrinsic electrophysiological properties in LMAN studied to date, only the half-height spike width continues to change in the late juvenile stages of song learning. Furthermore raising juveniles in isolation from an adult tutor transiently delays the maturation of this property. The present results underscore that beyond their effects on LMAN's synaptic properties, both androgens and adult tutor experience are potent and selective regulators of the intrinsic properties of LMAN neurons.

Action Potentials↗

PubMed2000

Bird communication: two voices are better than one.

How do emperor penguins find their mates on a featureless ice flow, packed at densities of ten animals per square meter? A recent study has revealed how use of their 'two-voice' calls enables emperor penguins to locate their mates and chicks under some of nature's most extreme conditions.

Animal Communication↗

PubMed2000

Different subthreshold mechanisms underlie song selectivity in identified HVc neurons of the zebra finch.

Songbirds learn and maintain their songs via auditory experience. Neurons in many telencephalic nuclei important to song production and development are song selective, firing more to forward auditory playback of the bird's own song (BOS) than to reverse BOS or conspecific songs. Elucidating circuits that generate these responses can localize where auditory experience influences vocalization, bridging cellular and systems analyses of song learning. Song-selective responses in many song nuclei, including the vocal premotor nucleus robustus archistriatalis (RA) and the basal ganglia homolog area X, are thought to originate in nucleus HVc (used as a proper name), which contains interneurons and relay cells that innervate either RA or area X. Previous studies indicated that only X-projecting neurons have auditory responses, leaving open the source of RA's auditory input and the degree to which song selectivity may be refined in HVc. Here, in vivo intracellular recordings from morphologically and electrophysiologically identified HVc neurons revealed that both relay cell types fire song-selectively. However, their firing arises via markedly different subthreshold processes, and only X-projecting neurons appear to be sites for auditory refinement. RA-projecting neurons exhibited purely depolarizing subthreshold responses that were highly song selective and that were excitatory. In contrast, subthreshold responses of X-projecting neurons included less-selective depolarizing and highly selective hyperpolarizing components. Within individual birds, these BOS-evoked hyperpolarizations closely matched interneuronal firing, suggesting that HVc interneurons make restricted inputs onto X-projecting neurons. Because of the two relay cell types' subthreshold differences, factors affecting their resting membrane potentials could enable them to transmit distinct song representations to their targets.

Acoustic Stimulation↗

PubMed2000

Intrinsic and extrinsic contributions to auditory selectivity in a song nucleus critical for vocal plasticity.

The development, maintenance, and perception of learned vocalizations in songbirds are likely to require auditory neurons that respond selectively to song. Neurons with song-selective responses have been described in several brain nuclei critical to singing, but the mechanisms by which such response properties arise, are modified, and propagate are poorly understood. The lateral magnocellular nucleus of the anterior neostriatum (LMAN) is the output of an anterior forebrain pathway (AFP) essential for learning and maintenance of song, processes dependent on auditory feedback. Although neurons throughout this pathway respond selectively to auditory presentation of the bird's own song, LMAN is the last stage at which responses to this auditory information could be transformed before being transmitted to vocal motor areas, where such responses may influence vocal production. Indeed, previous extracellular studies have indicated that LMAN's auditory selectivity is greater than that at earlier stages of the AFP. To determine whether LMAN local circuitry transforms or simply relays song-related auditory information to vocal control neurons, it is essential to distinguish local from extrinsic contributions to LMAN's auditory selectivity. In vivo intracellular recordings from LMAN projection neurons, coupled with local circuit inactivation, reveal that much of LMAN's song selectivity is supplied by its extrinsic inputs, but selective blockade of GABA receptors indicates that local inhibition is required for the expression of song selectivity. Therefore, LMAN neurons receive highly song-selective information, but LMAN's local circuitry can mask these selective inputs, providing a mechanism for context-dependent auditory feedback.

Acoustic Stimulation↗

PubMed2000

Slow NMDA-EPSCs at synapses critical for song development are not required for song learning in zebra finches.

Birdsong, like human speech, is learned via auditory experience during a developmentally restricted sensitive period. Within projection neurons of two avian forebrain nuclei, NMDA receptor-mediated EPSCs (NMDA-EPSCs) become fast during song development, a transition posited to limit learning. To discover whether slow NMDA-EPSCs at these synapses are required for learning, we delayed song learning beyond its normal endpoint, post-hatch day (PHD) 65, by raising zebra finches in isolation from song tutors. At PHD45, before learning, isolation delayed NMDA-EPSC maturation, but only transiently. By PHD65, NMDA-EPSCs in isolates were fast and adult-like, yet isolates presented with tutors readily learned song. Thus song learning did not require slow NMDA-EPSCs at synapses critical for song development.

Acoustic Stimulation↗

PubMed2000

Involvement of energy metabolism in the production of 'bystander effects' by radiation.

These experiments were done to determine if interference with energy metabolism and REDOX biochemistry during low LET radiation exposure would alter the ability of medium harvested from the irradiated cells to induce a bystander effect in unirradiated cells. Human keratinocyte cells and CHO-K1 mutant cell lines were irradiated using cobalt 60. Clonogenic assays were used to determine the reproductive death of the cells exposed to direct irradiation or medium from irradiated cells. The persistence in progeny was also examined. Use of apoptosis inhibitors or medium from the LDH or G6PD null cell lines, reduced or prevented the bystander effect. Transfection with G6PD recovered the effect. Treatment with anti-oxidant substances, L-lactate and L-deprenyl prevented bystander factor associated cell kill. The lactate analogue, oxamate, was less effective. Data from experiments where media harvested from the different cell lines was exchanged suggest that signal production and cellular response may involve different mechanisms. The effects on exposed cells were transmitted to progeny which also showed excessive levels of cell death for several generations. The results suggest that energy/REDOX metabolism may be involved in the expression of a radiation induced bystander response. Given the aberrant energy metabolism in tumour cells, this may have implications for dose escalation in radiotherapy.

Animals↗

PubMed1999

Lesions of an avian forebrain nucleus that disrupt song development alter synaptic connectivity and transmission in the vocal premotor pathway.

The avian forebrain nucleus, the lateral magnocellular nucleus of the anterior neostriatum (LMAN), is necessary for normal song development because LMAN lesions made in juvenile birds disrupt song production but do not disrupt song when made in adults. Although these age-limited behavioral effects implicate LMAN in song learning, a potential confound is that LMAN lesions could disrupt normal vocal motor function independent of any learning role by altering LMAN's premotor target, the song nucleus, the robust nucleus of the archistriatum (RA). To date, however, no studies have examined directly the effects of LMAN lesions on the circuitry of the RA. We report here that juvenile LMAN lesions rapidly and profoundly affect RA, altering synaptic connectivity within this nucleus, including descending inputs from the song nucleus HVc. Specifically, morphological assays of the dendritic spines of RA projection neurons and axon terminal boutons arising from HVc show a numerical decline in the density of connections in RA in LMAN-lesioned juveniles compared with controls. Concurrently, LMAN lesions alter excitatory transmission within the juvenile RA: after LMAN lesions, the stimulus-response relationship between HVc fibers and RA neurons steepens, and the amplitude of spontaneous monophasic EPSCs increases. Rather than arresting RA in a juvenile state, LMAN lesions transform the structure and function of RA and its connections, such that it is distinct from that of the normal juvenile. In many ways, RA circuitry in LMAN-lesioned juveniles resembles that of normal adults, suggesting that LMAN lesions induce a premature maturation of the vocal motor pathway, which may lead to a loss of behavioral plasticity and abnormal song development.

Aging↗

PubMed1999

Can an old bird change his tune?

The stereotyped courtship songs of 'age-limited' songbirds, which learn their songs during a specific early period of their lives, were once thought immutable, but recent studies suggest that their maintenance may actually rely on subtle cues provided by auditory feedback.

Acoustic Stimulation↗

PubMed1999

Hypoketotic hypoglycemic coma in a 21-month-old child.

We present the case of a 21-month-old child with hypoketotic hypoglycemic coma. The differential diagnosis initially included metabolic causes versus a toxicologic emergency (unripe ackee fruit poisoning). Using information obtained from the emergency department, the diagnosis was confirmed as the late-onset form of glutaric acidemia type II. This case illustrates the importance of emergency physicians in the diagnosis and management of children with inborn errors of metabolism.

Acidosis↗

PubMed1999

Sensitive periods and circuits for learned birdsong.

Experience influences the development of certain behaviors and their associated neural circuits during a discrete period after birth. Songbirds, with their highly quantifiable vocal output and well-delineated vocal control circuitry, provide an excellent context in which to examine the neural mechanisms regulating sensitive periods for learning. Recent discoveries indicate that auditory input to the vocal control circuitry in songbirds is dynamically modulated and show that neural circuitry previously thought to be used only in plastic juvenile song may also actively maintain stable adult song. These findings provide important clues to how sensitive periods for auditory feedback and vocal plasticity are regulated during song development.

Age Factors↗

PubMed1999

Stimulation of transposition of the Mycobacterium tuberculosis insertion sequence IS6110 by exposure to a microaerobic environment.

The Mycobacterium tuberculosis-specific insertion sequence IS6110/986 has been widely used as a probe because of the multiple polymorphism observed among different strains. To investigate transposition of IS6110, a series of artificially constructed composite transposons containing IS6110 and a kanamycin resistance marker were constructed. The composite transposons were inserted into a conditionally replicating, thermosensitive, Escherichia coli-mycobacterial shuttle vector and introduced into M. smegmatis mc2155. Lawns of transformants were grown at the permissive temperature on kanamycin-supplemented agar and subsequently prevented from further growth by shifting to the non-permissive temperature. Under normal atmospheric conditions, kanamycin-resistant papillae appeared after only about 5-6 weeks of incubation. However, these events were not associated with transposon mobilization. In contrast, lawns that were exposed to a 48 h microaerobic shock generated kanamycin-resistant papillae after only 6-14 days. These events were generated by conservative transposition of the IS6110 composite transposon into the M. smegmatis chromosome, with loss of the shuttle vector. In common with other IS3 family elements, transposition of IS6110 is thought to be controlled by translational frameshifting. However, we were unable to detect any significant frameshifting within the putative frameshifting site of IS6110, and the level of frameshifting was not affected by microaerobic incubation. The finding that transposition of IS6110 is stimulated by incubation at reduced oxygen tensions may be relevant to transposition of IS6110 in M. tuberculosis harboured within TB lesions.

Adaptation, Physiological↗

PubMed1999

Long-range inhibition within the zebra finch song nucleus RA can coordinate the firing of multiple projection neurons.

The zebra finch forebrain song control nucleus RA (robust nucleus of the archistriatum) generates a phasic and temporally precise neural signal that drives vocal and respiratory motoneurons during singing. RA's output during singing predicts individual notes, even though afferent drive to RA from the song nucleus HVc is more tonic, and predicts song syllables, independent of the particular notes that comprise the syllable. Therefore RA's intrinsic circuitry transforms neural activity from HVc into a highly precise premotor output. To understand how RA's intrinsic circuitry effects this transformation, we characterized RA interneurons and projection neurons using intracellular recordings in brain slices. RA interneurons fired fast action potentials with steep current-frequency relationships and had small somata with thin aspinous processes that extended throughout large portions of the nucleus; the similarity of their fine processes to those labeled with a glutamic acid decarboxylase (GAD) antibody strongly suggests that these interneurons are GABAergic. Electrical stimulation revealed that RA interneurons receive excitatory inputs from RA's afferents, the lateral magnocellular nucleus of the anterior neostriatum (LMAN) and HVc, and from local axon collaterals of RA projection neurons. To map the functional connections that RA interneurons make onto RA projection neurons, we focally uncaged glutamate, revealing long-range inhibitory connections in RA. Thus these interneurons provide fast feed-forward and feedback inhibition to RA projection neurons and could help create the phasic pattern of bursts and pauses that characterizes RA output during singing. Furthermore, selectively activating the inhibitory network phase locks the firing of otherwise unconnected pairs of projection neurons, suggesting that local inhibition could coordinate RA output during singing.

Amygdala↗

PubMed1999

Androgens modulate NMDA receptor-mediated EPSCs in the zebra finch song system.

Androgens potently regulate the development of learned vocalizations of songbirds. We sought to determine whether one action of androgens is to functionally modulate the development of synaptic transmission in two brain nuclei, the lateral part of the magnocellular nucleus of the anterior neostriatum (LMAN) and the robust nucleus of the archistriatum (RA), that are critical for song learning and production. We focused on N-methyl-D-aspartate-excitatory postsynaptic currents (NMDA-EPSCs), because NMDA receptor activity in LMAN is crucial to song learning, and because the LMAN synapses onto RA neurons are almost entirely mediated by NMDA receptors. Whole cell recordings from in vitro brain slice preparations revealed that the time course of NMDA-EPSCs was developmentally regulated in RA, as had been shown previously for LMAN. Specifically, in both nuclei, NMDA-EPSCs become faster over development. We found that this developmental transition can be modulated by androgens, because testosterone treatment of young animals caused NMDA-EPSCs in LMAN and RA to become prematurely fast. These androgen-induced effects were limited to fledgling and juvenile periods and were spatially restricted, in that androgens did not accelerate developmental changes in NMDA-EPSCs recorded in a nonsong area, the Wulst. To determine whether androgens had additional effects on LMAN or RA neurons, we examined several other physiological and morphological parameters. In LMAN, testosterone affected alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate-EPSC (AMPA-EPSC) decay times and the ratio of peak synaptic glutamate to AMPA currents, as well as dendritic length and spine density but did not alter soma size or dendritic complexity. In contrast, testosterone did not affect any of these parameters in RA, which demonstrates that exogenous androgens can have selective actions on different song system neurons. These data are the first evidence for any effect of sex steroids on synaptic transmission within the song system. Our results support the idea that endogenous androgens limit sensitive periods for song learning by functionally altering synaptic transmission in song nuclei.

Aging↗