0%), and psychosis (41, 9.4%; specified as first onset by clinicians based on no prior episodes and being within 3 months of first contact with the health service). Full BRISC In the total sample (n = 1079), negativity–positivity bias scores correlated negatively and significantly with both emotional resilience (r = −0.499; P < 0.0001) and social skills (r = −0.279; P < 0.0001; Table 2). These correlations are consistent with the theoretical basis of the BRISC: that the marker of risk (negativity bias) will be inversely related to markers

of coping (emotional resilience and social skills). Emotional resilience and social skills were found to have a significant overlap (r = 0.312; P < 0.0001). The degree of Inhibitors,research,lifescience,medical overlap is consistent with these markers, reflecting partially separable types of protective factors. Table 2 Correlations between scores on the 45-question BRISC Inhibitors,research,lifescience,medical and 15-question mini-BRISC* ROC analyses In ROC analyses, negativity bias made the largest contribution to classification. Figure 2 shows the breakdown of clinically confirmed diagnoses for negativity Inhibitors,research,lifescience,medical bias in the “clinical” group. Sensitivity of the BRISC was highest for depression, posttraumatic stress disorder, and panic disorder, followed by psychosis, brain injury, and mild cognitive impairment. Figure 2 45-Item BRISC. Breakdown of classification by diagnosis for negativity bias using the ROC determined threshold. Table 3 shows the ROC curve analysis Bcl-2 pathway results across

negativity bias, emotional resilience, social skills, and combined total scores for Inhibitors,research,lifescience,medical the 45-item BRISC. Table 3 Summary of sensitivity, specificity, and positive and negative predictive power of the 45-question BRISC scores at z-score thresholds of −2, −1.5, −1, and −0.5 and ROC determined optimal score For the negativity bias score, the optimal z-score threshold for distinguishing clinical status was −1.14. This threshold was both sensitive (84.9%) and specific (87.6%) in classifying the clinical versus healthy groups. In addition to good positive predictive Inhibitors,research,lifescience,medical power at this threshold (70.7%), there was also high negative predictive power (94.3%; Table 3). The AUC value

of 0.92 indicated a very high discrimination, reflective of overall accuracy. Emotional resilience scores revealed a lower optimal threshold of z = −0.43 for distinguishing clinical from healthy status. Sensitivity was at 69.3% and specificity was at 70.0%. The results most suggested that these scores contribute most to negative predictive power (81.7%) for supporting decisions about confirming good emotional health (Table 3). Overall accuracy was high (AUC was 0.75). Social skills scores had an optimal threshold of z = −0.50 for classifying clinical from healthy groups. Sensitivity was at 54.6% and specificity was at 68.1%. Results for these scores suggest that they contribute most to negative predictive power (80.9%) relevant to the confirmation of healthy status (Table 3). These scores contributed to a good overall accuracy (AUC was 0.

We found that the formation of amyloid -like huntingtin fibrils in vitro and in vivo critically depends on polyglutamine repeat length, protein concentration, and time. Furthermore, huntingtin aggregation can be seeded by preformed fibrils, suggesting that fibrillogenesis in HD, as in Alzheimer’s disease, is caused by nucleation-dependent polymerization.43 Our findings that the assembly of huntingtin aggregates requires the formation of a nucleus and is time- and protein concentration-dependent may account for the late onset and progressive phenotype in HD. Although fibril formation occurs within hours in the in vitro system, it may take years in neuronal cells of HD patients.

The concentration Inhibitors,research,lifescience,medical of mutant huntingtin in medium spiny neurons, which are affected most in HD, is unknown, but it is likely to be much lower than that used in the in vitro aggregation assays. Thus, we Inhibitors,research,lifescience,medical suggest that the lag time during which huntingtin dinners, trimers,

and oligomers are formed in vivo is significantly elongated in HD patients. For the identification of huntingtin aggregation inhibitors, we have developed a rapid and sensitive filter retardation assay, which is suitable for the highthroughput screening of drugs that prevent aggregate formation.45 Inhibitors,research,lifescience,medical This assay is based on the finding that HD exon 1 aggregates are insoluble in sodium dodecyl sulfate (SDS) and are retained on a cellulose acetate filter, whereas monomelic forms of the HD exon 1 protein do not bind to this filter membrane. The captured aggregates Inhibitors,research,lifescience,medical are then detected by simple immunoblot analysis using a specific anti-huntingtin antibody. Using the filter retardation assay, we first tested a number of known inhibitors of β-amyloid, PrPscr, and microtubule fibril formation for their effect on huntingtin aggregation in vitro.46 We found that Congo red, thioflavine S, chrysamine G, and Direct fast yellow inhibited HD exon 1 protein aggregation in a dose-dependent manner, whereas other potential inhibitors of β-amyloid Inhibitors,research,lifescience,medical formation, such as thioflavine T, gossypol, melatonin, and rifampicin, had little or no effect on huntingtin aggregation. The results obtained in vitro

were confirmed in cell culture model systems. Furthermore, we found that the monoclonal antibody 1C2, which specifically recognizes the elongated polyglutamine stretch in huntingtin, and the heat almost shock proteins Hsp70 and Hsp40 are potent inhibitors of huntingtin aggregation.46, 47 Interestingly, the addition of heat shock proteins to in vitro aggregation reactions shifts the self-association pathway of huntingtin from fibrillar to amorphous aggregation. This suggests that in vivo chaperones may have the potential to transform toxic fibrillar aggregates into nontoxic aggregates, which can then be Daporinad cost degraded by the ubiquitin/proteasome system. Thus, small molecules that activate a heat shock response in neurons may be effective in delaying the onset and progression of HD.

Moreover, we must take into account that, like the pathophysiological mechanisms of complex psychiatric disorders, different genes are interacting and modulating each other in drug response, in addition

to environmental factors. Nevertheless, the field of pharmacogenetics is expanding rapidly, and the elucidation of the disease processes through Inhibitors,research,lifescience,medical genomics, the identification of novel drug targets, and the subtyping of patient populations are all ambitious methods that may help us individualize pharmacological therapy. Conclusion Understanding the biology of major depression is a challenging scientific problem with enormous sociological and clinical relevance. The discovery of antidepressant drugs and the investigation of their mechanism of action has revolutionized our understanding of neuronal functioning and the possible mechanisms underlying depression. There is no doubt that the monoaminergic system is one Inhibitors,research,lifescience,medical of the cornerstones of research, but any hypothesis

for the pathophysiology of depression must take into account the many interactions with other brain systems and the complexity of the regulation of the CNS function. In spite of all the progress that has been achieved in the last Inhibitors,research,lifescience,medical decades, we must be aware that there are still today considerable problems in understanding and treating severe depression, and knowing the cause of treatment-resistant depression. Selected abbreviations

and acronyms BDNF brain-derived neurotrophic factor CRH corticotropin-releasing hormone DA dopamine GABA γ-aminobutyric acid GH growth hormone HPA hypothalamus-pituitary-adrenal Inhibitors,research,lifescience,medical S-HT 5-hydroxy try ptamine (serotonin) MAOI monoamine oxidase inhibitor NE norepinephrine NK natural killer (cell) SSRI selective serotonin-reuptake inhibitor TCA tricyclic antidepressant
Stress-related psychiatric disorders such as anxiety and major depression impair the lives of approximately Inhibitors,research,lifescience,medical 10% to 15% of the population. For many years, the success of the pharmacological treatment of these disorders has been restrained by various PF-04691502 ic50 factors, including long latency of clinical effect, treatment Ketanserin resistance, adverse side effects, and, in the case of the anxiolytic benzodiazepines, tolerance and addictive potential. Although stress has continuously been a subject of research since the 1940s, the pharmacological principle of action (ie, the interaction with the classic neurotransmitters such as serotonin, noradrenaline, and γ-aminobutyric acid [GABA]) of the antidepressant and anxiolytic drugs prescribed today still stems from work carried out as early as the 1950s. A new epoch began in 1981 with the discovery of corticotropin-releasing hormone (CRH) as the principal mediator of the effects of stress on the hypothalamicpituitary-adrenocortical (HPA) axis and behavior.

Cerebral perfusion imaging using SPECT may also be useful in predicting

subsequent BMS 345541 dementia among patients with MCI.112,113 Functional magnetic resonance imaging Brain activity following a stimulus can be localized with fMRI, a technique that is sensitive to the small changes in blood oxygenation associated with increased regional metabolic demand. Using visual memory Inhibitors,research,lifescience,medical tests to activate the medial temporal lobe, MCI subjects were found to exhibit a smaller fMRI response than cognitively normal subjects, though differences between MCI and AD were not detected.114 Another fMRI study found poor activation within the hippocampus in all MCI subjects, while some had normal entorhinal cortex responses suggesting anatomical heterogeneity with respect to memory processing.115 A recent MCI study116 found that visual memory test performance correlated with medial temporal lobe activation but, surprisingly, activation was more extensive in patients who developed dementia compared with those who remained stable. Like PET and structural MRI studies, nondemented patients at high genetic Inhibitors,research,lifescience,medical risk for dementia may exhibit decreased patterns of brain activation compared with controls.117 Magnetic resonance spectroscopy Using proton MRS (1H-MRS), several

groups have found brain metabolite Inhibitors,research,lifescience,medical concentrations for 7V-acetylaspartate (NAA) and myoinositol (MI) to distinguish AD patients from controls although conflicting results have been reported for choline.118 Decreased NAA concentration relative to creatine (NAA/Cr) is considered to be an MRS marker of diminished neuronal density and viability. Elevations in Ml/Cr ratios are less specific, but may be associated with glial activation and other neurochemical processes; Inhibitors,research,lifescience,medical it is unclear how this may relate to AD pathogenesis. Compared

with normal controls, some investigators have found increased Ml/Cr in the posterior cingulate gyrus and white matter of MCI patients.119,120 Nondemented Down’s syndrome patients at high risk for AD also have elevated Ml/Cr ratios.121 A recent study observed that decreased medial temporal lobe NAA/H2O Inhibitors,research,lifescience,medical ratios distinguished MCI patients from normal controls, while increased parietotemporal MI/H2O distinguished MCI cases from AD.122 Further research will determine whether MRS can identify a specific metabolite signature that differentiates Idoxuridine early AD pathology. Some evidence, however, suggests that while NAA/Cr may be a nonspecific marker for age-related neuronal dysfunction and cognitive decline, MI elevations may be a better index of neuropathology.123 Imaging AD pathology Recently developed amyloid imaging tracers for PET have resulted in pilot studies with promising initial findings.124,125 The positron-emitting [11C]benzothiazole derivative known as Pittsburgh compound-B (PIB) has been shown to effectively discriminate a group of 16 mild AD patients from cognitively normal controls in a recently published PET study.

A pharmacokinetic study of quetiapine in adolescents with psychotic disorders demonstrated slightly higher quetiapine exposure in adolescents than in adults.113 Quetiapine had a beneficial effect on positive and negative symptoms and was well tolerated; the most common AEs were insomnia and postural tachycardia. Ziprasidone was released on the US market in March 2001. Inhibitors,research,lifescience,medical No controlled data on ziprasidone treatment for COS have been published. However, a placebo-controlled study

of ziprasidone (5-40 mg/day) was carried out in 28 children and adolescents (aged 7-17 years) with Tourette’s syndrome.114 Somnolence and EPSs were rare and resolved with dose decrease: 1 subject had brief but Inhibitors,research,lifescience,medical severe somnolence on 40 mg/day, and 1 subject experienced akathisia on 40 mg/day. No significant weight gain was noted in subjects. Adverse effects The relative impact of neuroleptics at various receptor types determines the AEs. Depending on which dopamine receptor D2 tracts are blocked, AEs of neuroleptics include EPS (nigrostriatal pathway), increased negative symptoms (mesocortical pathway), and hyper prolactinemia (tuberoinfundibular pathway). Inhibitors,research,lifescience,medical Prolactin levels were studied in 35 children and adolescents

with COS treated with haloperidol, olanzapine, and/or clozapine.115 After 6 weeks of treatment, all subjects on haloperidol and 70% of subjects on olanzapine showed increased prolactin above the upper limits of normal, whereas Inhibitors,research,lifescience,medical no subjects on clozapine showed increased prolactin level. In addition to an impact on D2, typical neuroleptics have an anticholinergic effect (muscarinic acetylcholine receptor, M1) including sedation, dry mouth, blurry vision, and constipation; an antihistaminergic effect (histamine receptor, H1) including sedation and weight gain; and antiadrenergic effects (adrenergic Inhibitors,research,lifescience,medical receptor, α1 including dizziness and hypotension. TKI-258 research buy Atypical neuroleptics also have capacity to impact M1, H1( and

α1 receptors, and may additionally block D1, D2, and D4, as well as the serotonin (5-hydroxytryptamine) receptors 5-HT3,5-HT2C, and 5-HT3. In vitro data suggest that the atypical agents have unique receptor blockade selectivity. For instance, clozapine blocks all of the above receptors, whereas risperidone blocks only 5-HT2A, 5-HT2C, α1, and D2 receptors. Serotonergic blockade by atypical neuroleptics appears to ever modify antipsychotic effect and AEs related to dopamine blockade, and it may have a mood-stabilizing effect. Significant prolongation of QTC duration (Q-T interval adjusted for rate) is associated with butyrophenoncs, phenothiazines, and pimozide, and does not appear to be clearly associated with any of the atypical neuroleptics.116 However, electrocardiographic monitoring of QTC intervals is recommended with ziprasidone.

Memory tasks where age invariance has been demonstrated include picture recognition28

and implicit memory29-31 – both passive, nonstratcgic tasks. Also, there is some evidence that age differences are more pronounced for encoding new material, compared with retrieving information,32,33 due to the obligatory or automatic nature of retrieval.34 Finally, knowledge organization and semantic memory remain relatively unchanged with age.35,36 Figure 1 demonstrates that world knowledge, as measured by vocabulary, is not subjected to age-related declines, and may even show growth across the life span. As Figure 1 illustrates, it is only Inhibitors,research,lifescience,medical tasks that require considerable mental effort or deliberate recollection that show age declines.37 Inhibitors,research,lifescience,medical Repairing declining cognition The primary view of how to “repair” declining cognition among cognitive aging psychologists has been to provide older adults with memory supports that bypass the need to encode items actively or deliberately, thus lessening the executive processing requirements of the tasks.38 Specific examples in which environmental supports have effectively repaired the memory of older adults include (i) using

matching pictures to support memory for sentences, resulting in dramatically better memory in older adults (probably due to dual coding of the material, which provides Inhibitors,research,lifescience,medical two routes to recall39); and (ii) providing older adults with memory cues that Inhibitors,research,lifescience,medical are conceptually related to target words, resulting in click here larger memory improvements for the words in the old compared with the young.40 The conceptually related cues built upon existing world knowledge possessed by older adults, and

relied on activation of existing Inhibitors,research,lifescience,medical information rather than only on engagement of executive processes (primarily working memory). Neural underpinnings of cognitive aging Recently, the fields of neurosciencc and cognitive aging have begun to merge, and we have already learned a number of things that were not previously considered in a systematic way in the cognitive aging literature. In the following sections, we discuss what is known about neural decline and reorganization, as it relates to aging. only Brain atrophy Structural imaging of brains indicate that, although the brain shrinks or shows volumetric changes with age, these changes are not equal across brain structures. There is more shrinkage with age in the frontal cortex, intermediate shrinkage in mediotemporal areas, and little decrease in volume in the occipital cortex.41 There are decreases in both gray matter and white matter, and evidence for demyclination.41,42 Increases in white matter hyperintensities occur with age.43 These are small decreases in white matter tissue irregularly distributed across regions.

2.2.7. Polyacrylic and Polyvinyl Polymers Synthetic polyacrylic and polyvinyl polymers bearing hydrophobic moieties have been prepared to coat liposomes. The hydrophobic function allows for the polymer anchoring on the particle surface.

Palmitoyl- or phosphatidylethanolamine- (PE-) terminated derivatives of poly(acryl amide) (PAA), poly(vinyl pyrrolidone) (PVP), and poly(acryloyl morpholine) (PAcM) have been found to exert comparable stealth effects on liposomes in vivo. This behaviour depends on the length of the hydrophobic Inhibitors,research,lifescience,medical alkyl function, the polymer molecular weight, and its surface density [88, 89]. Comparative studies performed with palmitoyl-or PE-functionalized 6–8kDa PAA, PVP, and PEG showed Inhibitors,research,lifescience,medical that the PEG derivative has slightly better performance as compared to the other polymers. Macromolecules containing shorter hydrophobic moieties than palmitoyl- or phosphatidylethanolamine-, namely, Inhibitors,research,lifescience,medical dodecyl alkyl chains, or higher polymer molecular weight (12–15kDa) showed a lower effect on circulation time of liposomes. Short hydrophobic moieties cannot efficiently anchor the polymer on the liposome surface as the energy of the polymeric chain motion is higher

than the energy of the anchoring alkyl chain interaction with the liposomal phospholipid bilayer [88, 90]. The Inhibitors,research,lifescience,medical higher the polymer molecular weight, the higher the free energy of the exposed polymer chains. Therefore, the polymer can detach in vivo inducing liposome opsonisation and removal by the RES [91]. The layer thickness of poly(vinyl Inhibitors,research,lifescience,medical alcohol)s (6, 9, and 20kDa PVA) derivatized with C16H33–S– as hydrophobic anchor (PVA-R) on the liposome surface was directly proportional to the polymer molecular weight and to the concentration of the polymer solution used

for the coating process. Furthermore, it was found that the PVA-R density on the liposome surface increased as the molecular weight of the polymer decreased. The PVA-R on liposomes was not detached by dilution or in presence of serum while preventing the adsorption of plasma proteins. In vivo the PVA-R-BIX 01294 supplier coated liposomes showed prolonged permanence Chlormezanone in the circulation, which increased as the PVA molecular weight increased. The circulation time of liposomes coated with 1.3% mol of 20kDa PVA-R was comparable to that of liposomes coated with 8% mol of 2kDa PEG-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG-DSPE). Detailed investigations showed that the increased permanence in the bloodstream was strictly related to the PVA-R stability on the liposome surface that was higher compared to PEG-DSPE [92]. 2.3.

Clinically meaningful laboratory applications in the future will need to overcome significant barriers. Currently, there are not widely accepted methods and standards for performing genomic analysis using array platforms. There is also wide variation in the analytical and computational methods used in comparative genomic analysis. In addition, there is a paucity Inhibitors,research,lifescience,medical of standardized control biomaterials for use in analyses. Finally all of these quantitative

measures are highly sensitive to clinical specimen acquisition, preparation, and storage methods. Little comparative work on standards for controls and disease biospecimens has been done on establishing normal datasets for gene expression methods. Recently, a summary of these issues was addressed through a guidance document issued by the Centers for Disease Control and Prevention (CDC).17 The lack of highly annotated and fully characterized biospecimens with longitudinal phenotypic and demographic information remains a significant barrier for all of translational research Inhibitors,research,lifescience,medical in personalized medicine, but is most notable in large-scale genomic analyses.18 The application of the various genomic technology platforms has led to transformative Inhibitors,research,lifescience,medical research in population genetics.

Over the last several years, population-based research studies, such as the Framingham Heart Study, have enabled large-scale genomic analyses from clinical resources. Collectively, these genome-wide association http://www.selleckchem.com/products/H-89-dihydrochloride.html studies (GWAS), have enabled cross-study analyses from

Inhibitors,research,lifescience,medical publicly available databases known as dbGAP (database of genotype and phenotype).19 Over the past several years, hundreds of new GWAS results have yielded insights into multigene effects to a wide variety of human Inhibitors,research,lifescience,medical diseases and conditions. Many of these new mutations are identified in noncoding regions. Collectively, the discovery of these new associations is prompting more hypothesis generation about disease pathways than generating platforms for new diagnostics and therapeutics. These public resources are proving to be useful discovery resources for various disease areas, such as enough psychiatry, enabling consortia of investigators to use statistical analytic methods to map genetic architecture of common disorders.20 Information technologies in health care and impact on personalized medicine A key infrastructure needed to establish a medical practice environment for individualized decision making is a robust and facile information technology capability. The reasons for this are the dependency on key attributes about the patient’s health status, detailed data needs for phenotypic characteristics, and the complexity of the types of analytical data and decision algorithms that will be used to support more precise, preferred, and predictive health outcomes for the patient.

51 Ketamine

also increases the function of these new synapses shown by an increase in the amplitude and frequency of 5-hydroxytyramine (5-HT)- and hypocretin-induced excitatory postsynaptic currents in layer V pyramidal neurons in the medial PFC. Ketamine increases levels of synaptic proteins after 2 hours, indicating an increase in synapse number, a time that corresponds to the initial therapeutic response in humans.51 Ketamine also produces antidepressant behavioral responses in the forced swim test (decreased immobility or despair) and novelty suppressed feeding (decreased Inhibitors,research,lifescience,medical latency to feed in an open field). Moreover, a single dose of ketamine clinical trial reverses the deficit in the number of synapses caused by exposure to 3 weeks of chronic unpredictable stress (CUS).52 This corresponds with the rapid reversal of the Inhibitors,research,lifescience,medical CUS-precipitated behavioral deficit, anhedonia, which is measured by a decrease in preference for sweetened solution. Together, these findings Inhibitors,research,lifescience,medical demonstrate a novel rapid action of ketamine, the induction of synaptic connections that reverses the effects of CUS and corresponds to an antidepressant behavioral response that requires chronic administration of a typical antidepressant. Assuming that a similar synaptogenic response occurs in humans, a question of intense interest, ketamine would then reverse the atrophy

and synaptic deficits that are a critical pathophysiological component Inhibitors,research,lifescience,medical of depression. Indirect support for this hypothesis is provided by a recent clinical study, using magnetoencephalographic recordings, before and after ketamine infusions, in depressed patients and during somatosensory cortex activation (ie, tactile Inhibitors,research,lifescience,medical stimulation of index fingers).53 The results show that cortical excitability is increased in responders during the period of antidepressant response (≈4 hours after ketamine), but not in those patients who did not respond to ketamine. There was no effect Bay 11-7085 of ketamine on baseline γ-band activity, suggesting that the acute NMDA receptor-blocking effects of ketamine do not account for the antidepressant responses. Rather, the results are consistent with the possibility that increased glutamate activity and enhanced synaptic potentiation underlie the increase in cortical excitability, as well as the antidepressant response to ketamine.53 It is possible that NMDA receptor blockade of glutamate transmission contributes to the therapeutic actions of ketamine, although this would be rapid and transient (ie, when the drug is present in the brain and during the time frame for the psychotomimetic effects, 30 to 60 minutes after dosing) and therefore would not correspond to the delayed time of the therapeutic response (80 to 120 minutes).

2A). At both sides of A3, the primary neurite gave off a large anterior and a smaller posterior dendrite. The ipsilateral and contralateral dendrites branched out bilateral symmetrically in the very dorsal neuropile of A3. In each neuromere

of the three thoracic ganglia, one prominent anterior lifescience branch and one or two posterior branches arose from the main axon and projected dorsally toward the midline of the respective ganglion. A3-AO occurred as a bilateral pair of sibling neurons, and in all three neurobiotin-labeled specimen, the Inhibitors,research,lifescience,medical mirror-image sibling neuron was clearly stained as well (Fig. 3). Such dye coupling may indicate electrical coupling between the left and right A3-AO interneuron via gap junctions (cf. Ewadinger et al. 1994; Fan et al. 2005; Anava et al. 2009). Figure 2 Structure and activity of the

abdominal ascending opener-interneuron A3-AO. (A) Morphology of A3-AO with cell body and dendrites in A3 and axonal projections in thoracic ganglia (ventral view). (B–D) Inhibitors,research,lifescience,medical Singing motor pattern (top trace) and activity … Figure 3 Dye coupling of the two A3-AO sibling neurons with neurobiotin. Extended focus views (maximum intensity projections of confocal image stacks) showing the fluorescence-labeled (neurobiotin-avidinCy3) arborizations of the two bilateral symmetrical A3-AO … During fictive singing, the membrane potential of A3-AO, as recorded in its main dendrite, oscillated with the syllable pattern (Fig. 2B). Inhibitors,research,lifescience,medical In the opener phase of each syllable, it depolarized by 20–25 mV, and in the closer phase, it hyperpolarized 5–10 mV beneath resting potential. The depolarization preceding the first syllable of a chirp was up to 3.5 mV higher than the following. Every depolarization gave rise to a volley Inhibitors,research,lifescience,medical of 4–6 action potentials with a spike frequency of up to 380 Hz during the first syllable and 360 Hz during the following syllables of a chirp. The spike activity Inhibitors,research,lifescience,medical in A3-AO preceded the next opener burst in the wing nerve by 10.1 ± 0.8 msec (mean ± SD; N = 10) and the following closer burst by 29.2 ± 2.2 msec (mean ± SD; N = 10). Therefore, we refer to A3-AO as an opener interneuron. Interestingly, we never observed any

synaptic inputs or spike activity in the A3-AO dendrite before and after singing episodes or during chirp intervals. When a constant depolarizing current of 5 nA was injected into the dendrite of A3-AO, the interneuron responded with consistently repeated depolarization–hyperpolarization oscillations of its membrane potential generating a burst Org 27569 of 2–6 action potentials during each depolarization. This rhythmic interneuron activity reliably elicited alternating opener–closer motoneuron activity reflecting the normal syllable pattern in the ipsi- and contralateral wing nerves. Activation of a single A3-AO interneuron is therefore sufficient to continuously drive the motor pattern of the syllable rhythm. Current pulses of 500 msec elicited long chirps with 14–15 syllables (Fig.