Differential effects of exposure to toxic or nontoxic mold spores on brain inflammation and Morris water maze performance.

People who live or work in moldy buildings often complain of "brain fog" that interferes with cognitive performance. Until recently, there was no published research on the effects of controlled exposure to mold stimuli on cognitive function or an obvious mechanism of action, fueling controversy over these claims. The constellation of health problems reported by mold-exposed individuals (respiratory issues, fatigue, pain, anxiety, depression, and cognitive deficits) correspond to those caused by innate immune activation following exposure to bacterial or viral stimuli. To determine if mold-induced innate immune activation might cause cognitive issues, we quantified the effects of both toxic and nontoxic mold on brain immune activation and spatial memory in the Morris water maze. We intranasally administered either 1) intact, toxic Stachybotrys chartarum spores; 2) ethanol-extracted, nontoxic Stachybotrys chartarum spores; or 3) control saline vehicle to mice. Inhalation of nontoxic spores caused significant deficits in the test of long-term memory of platform location, while not affecting short-term memory. Inhalation of toxic spores increased motivation to reach the platform. Interestingly, in both groups of mold-exposed males, numbers of interleukin-1ß-immunoreactive cells in many areas of the hippocampus significantly correlated with latency to find the platform, path length, and swimming speed during training, but not during testing for long-term memory. These data add to our prior evidence that mold inhalation can interfere with cognitive processing in different ways depending on the task, and that brain inflammation is significantly correlated with changes in behavior.

Defining the Scope of Knowledge Translation Within a National, Patient-Oriented Kidney Research Network.

PURPOSE OF PROGRAM: Integrated knowledge translation (IKT) is a collaborative approach whereby knowledge created through health research is utilized in ways that are relevant to the needs of all stakeholders. However, research teams have limited capacity and know-how for achieving IKT, resulting in a disconnect between the generation and application of knowledge. The goal of this report is to describe how IKT research was achieved across a large-scale, patient-oriented research network, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD). SOURCES OF INFORMATION: Resources to facilitate knowledge translation (KT) planning across the network were developed by the Can-SOLVE CKD Knowledge User/Knowledge Translation Committee with reference to established Canadian KT and patient engagement tools and frameworks, review of the published and gray literature, and expertise of committee members. METHODS: The Can-SOLVE CKD Knowledge User/Knowledge Translation Committee consisting of patient partners, health care providers, policymakers, and researchers provided oversight of the development and implementation of the network's IKT initiatives. Guided by its strategic framework, the committee developed KT planning templates and review checklists to assist network projects with preparing for dissemination, implementation, and scale and spread of their interventions. The committee has acted in a consultative capacity to facilitate IKT across network initiatives and has supported capacity building through KT activities aimed at network membership and knowledge users more broadly. KEY FINDINGS: The Can-SOLVE CKD Knowledge User/Knowledge Translation Committee established a nation-wide strategy for KT infrastructure and capacity building. Acting as a knowledge intermediary, the committee has connected research teams with knowledge users across Canada to support practices and policies informed by evidence generated by the network. The committee has developed KT initiatives, including a Community of Practice, whereby participants across different regions and disciplines convene regularly to share health research knowledge and communications strategies relevant to the network. Critically, patients are engaged and contribute throughout the research process. Examples of IKT activities from select projects are provided, as well as ways for sustaining the network's KT platform. LIMITATIONS: The KT resources developed by the committee were adapted from other established resources to meet the needs of the network and have not undergone formal evaluation in this context. Given the broad scope of the network, resources to facilitate implementation and knowledge user engagement may not meet the needs of all initiatives and must be tailored accordingly. Knowledge barriers, including a lack of information and skills related to conceptual and practical aspects of KT, among network members provided a rationale for various KT capacity-building initiatives. IMPLICATIONS: The approach described here offers a practical method for achieving IKT, including how to plan, implement, and sustain initiatives across large-scale health research networks. Within the context of Can-SOLVE CKD, these efforts will shorten knowledge-practice gaps through producing and applying relevant research to improve the lives of people living with kidney disease.

OBJECTIF DU PROGRAMME: L'application intégrée des connaissances (AIC) est une approche collaborative à répondre aux besoins de tous les intervenants. Les équipes de recherche ont cependant une capacité et un savoir-faire limités pour réaliser l'AIC, ce qui entraîne un décalage entre la production et l'application des connaissances. L'objectif de cet article est de décrire comment la recherche sur l'AIC a été réalisée dans le cadre d'un vaste réseau de recherche axée sur le patient, le réseau CAN-SOLVE CKD (Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease). SOURCES: Les ressources visant à faciliter la planification de l'application des connaissances (AC) dans l'ensemble du réseau ont été élaborées par le Comité des utilisateurs/de l'application des connaissances (Knowledge User/Knowledge Translation Committee) de Can-SOLVE CKD en se référant à des outils et des cadres d'AC et de participation des patients établis au Canada, à l'examen de la documentation publiée et de la littérature grise et à l'expertise des membres du comité. MÉTHODOLOGIE: Le Comité des utilisateurs/de l'application des connaissances de CAN-SOLVE, constitué de partenaires patients, de fournisseurs de soins, de décideurs et de chercheurs, a supervisé le développement et la mise en œuvre des initiatives d'AIC du réseau. Guidé par son cadre stratégique, le comité a élaboré des modèles de planification pour l'AC et des listes de vérification pour aider les projets du réseau à se préparer à la diffusion et à la mise en œuvre de leurs interventions, de même qu'à leur élargissement et leur diffusion. Le comité a agi à titre consultatif pour faciliter l'AIC dans l'ensemble des initiatives du réseau, et a appuyé le renforcement des capacités par le biais d'activités d'AC destinées aux membres du réseau et, plus largement, aux utilisateurs des connaissances. PRINCIPAUX RÉSULTATS: Le Comité des utilisateurs/de l'application des connaissances de CAN-SOLVE a établi une stratégie nationale pour l'infrastructure et le renforcement des capacités en matière d'AC. En tant qu'intermédiaire, le comité a mis en relation des équipes de recherche et des utilisateurs des connaissances partout au Canada afin d'appuyer les pratiques et les politiques fondées sur les données probantes produites par le réseau. Le comité a élaboré des initiatives d'AC, notamment une communauté de pratique où les participants des différentes régions et disciplines se réunissent sur une base régulière pour partager les connaissances générées en recherche et les stratégies de communication pertinentes pour le réseau. Il est essentiel que les patients s'engagent et contribuent tout au long du processus de recherche. Des exemples d'activités d'AIC tirés de projets sélectionnés sont fournis, de même que des moyens de maintenir la plateforme d'AC du réseau. LIMITES: Les ressources d'AC développées par le comité ont été adaptées à partir de ressources établies pour répondre aux besoins du réseau et, dans ce contexte, n'ont pas fait l'objet d'une évaluation officielle. Compte tenu de la vaste portée du réseau, les ressources destinées à faciliter la mise en œuvre et la participation des utilisateurs des connaissances pourraient ne pas répondre aux besoins de toutes les initiatives et devraient être adaptées en conséquence. Les freins à la connaissance parmi les membres du réseau, notamment le manque d'information et de compétences liées aux aspects conceptuels et pratiques de l'AC, ont servi de justification à diverses initiatives de renforcement des capacités en matière d'AC. CONCLUSION: L'approche décrite offre une méthode pratique pour parvenir à l'AIC, notamment dans la façon de planifier, de mettre en œuvre et d'appuyer des initiatives dans les réseaux de recherche d'envergure. Dans le contexte de CAN-SOLVE CKD, ces efforts permettront de réduire les écarts entre les connaissances et les pratiques, en produisant et en appliquant des recherches visant l'amélioration de la vie des personnes atteintes de néphropathies.

Mold inhalation causes innate immune activation, neural, cognitive and emotional dysfunction.

Individuals living or working in moldy buildings complain of a variety of health problems including pain, fatigue, increased anxiety, depression, and cognitive deficits. The ability of mold to cause such symptoms is controversial since no published research has examined the effects of controlled mold exposure on brain function or proposed a plausible mechanism of action. Patient symptoms following mold exposure are indistinguishable from those caused by innate immune activation following bacterial or viral exposure. We tested the hypothesis that repeated, quantified doses of both toxic and nontoxic mold stimuli would cause innate immune activation with concomitant neural effects and cognitive, emotional, and behavioral symptoms. We intranasally administered either 1) intact, toxic Stachybotrys spores; 2) extracted, nontoxic Stachybotrys spores; or 3) saline vehicle to mice. As predicted, intact spores increased interleukin-1ß immunoreactivity in the hippocampus. Both spore types decreased neurogenesis and caused striking contextual memory deficits in young mice, while decreasing pain thresholds and enhancing auditory-cued memory in older mice. Nontoxic spores also increased anxiety-like behavior. Levels of hippocampal immune activation correlated with decreased neurogenesis, contextual memory deficits, and/or enhanced auditory-cued fear memory. Innate-immune activation may explain how both toxic mold and nontoxic mold skeletal elements caused cognitive and emotional dysfunction.

Acoustic characteristics, early experience, and endocrine status interact to modulate female zebra finches' behavioral responses to songs.

Female songbirds use male songs as an important criterion for mate selection. Properties of male songs are thought to indicate the male's quality as a potential mate. Song preferences in female zebra finches are known to be influenced by two factors--early auditory experience and the acoustic characteristics of males' songs. Studies often investigate song preferences by priming females with estrogen. However, estrogenic influences on song preferences have not been studied. We investigated the relative influence of early auditory experience, acoustic features of songs, and estrogen availability on song responsiveness in female zebra finches. Juvenile female zebra finches were tutored for 10 days with 40 songs per day with one of three acoustically different song types--simple songs, long-bout songs or complex songs. A fourth group of females was untutored. Aside from this brief song exposure, females were raised and maintained without exposure to male songs. During adulthood, females' behavioral responses to the three song types were tested under three hormone conditions--untreated, estradiol-treated and 1,4,6-androstatriene-3,17-dione (ATD)-treated (to lower endogenous estrogen). Based on the results of our study, four conclusions can be drawn. First, song responsiveness in female zebra finches is strongly affected by minimal early acoustic experience. Second, inexperienced female zebra finches are inherently biased to respond more to complex songs over other song types Third, although female zebra finches are inherently biased to respond more to complex songs, early acoustic experience may either reinforce or weaken this inherent responsiveness to complex songs. Fourth, estrogen selectively accentuates song responsiveness in acoustically-experienced female zebra finches.

Noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), treatment eliminates estrogenic effects on song responsiveness in female zebra finches (Taeniopygia guttata).

Female songbirds use male songs as an important criterion for mate selection. Several studies have reported that female songbirds prefer complex songs to other song types. In a recent study, the authors found that song responsiveness in female zebra finches (Taeniopygia guttata) is strongly modulated by circulating estrogen levels. The behavioral effects of estrogen are often mediated via norepinephrine (NE). The current study administered the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) to estradiol-treated female zebra finches to investigate if estrogenic effects on song responsiveness are mediated via NE. The authors tested song responsiveness of adult female zebra finches for three acoustically different song types--simple, long-bout, and complex--under three treatment conditions, untreated, estradiol-treated, and estradiol + DSP-4-treated. Females only showed differential song responsiveness when treated with estradiol alone, responding more to complex songs. DSP-4 treatment eliminated this differential responsiveness. The results are discussed in the light of evidence from functional, neurochemical, and neuroanatomical studies that suggest that estrogenic effects on song processing might be mediated by NE.

Neurotoxic effects of DSP-4 on the central noradrenergic system in male zebra finches.

When administered systemically, the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) appears to target the noradrenergic innervation originating in the locus coeruleus causing long-term decrements in noradrenergic function. In songbirds, DSP-4-treatment decreased female-directed singing by males and copulation solicitation responses of females to male songs. However, DSP-4 treatment in songbirds did not lower measures of NE function in the brain to the same extent as it does in mammals. The current study had two goals: determining if two DSP-4 treatments 10 days apart would cause significant decrements in noradrenergic function in male zebra finches and determining if, as in other species, the noradrenergic innervation of midbrain and cortical areas would be profoundly affected while hypothalamic areas were spared. Dopamine-beta-hydroxylase immunoreactivity (DBH-ir) was quantified in thirteen brain regions (five vocal control nuclei, one auditory nucleus, two hypothalamic nuclei, and five additional areas that demonstrated high DBH labeling in controls). Within 20 days, DSP-4 treatment profoundly reduced the number of DBH-ir cells in both the locus coeruleus and ventral subcoeruleus. Unlike a previous study, DBH labeling delineated four out of five vocal control nuclei and an auditory nucleus. As expected, DSP-4 treatment significantly decreased DBH labeling in all areas examined in the mesencephalon and telencephalon without significantly affecting DBH-ir in hypothalamic areas. This double treatment regime appears to be much more effective in decreasing noradrenergic function in songbirds than the single treatment typically used.

Dopaminergic modulation of reproductive behavior and activity in male zebra finches.

We previously demonstrated that hormone treatments which stimulate female-directed singing increased levels and turnover of dopamine (DA) in brain areas controlling the motor patterning of song. To help determine how DA affects singing, we quantified the effects of treating adult male finches with the D1/D2 receptor antagonist cis-flupenthixol. Adult males were given subcutaneous silastic implants of androgen, in case drug treatment interfered with androgen secretion. One week later, they were tested with females. Males were divided into three groups matched for levels of courtship singing. Males were then subcutaneously implanted with osmotic minipumps containing either saline, a low, or a high dose of cis-flupenthixol. Each male was tested with a different female 5 and 10 days after implantation to determine how this D1/D2 receptor antagonist affected behavior. Both drug doses affected female-directed singing 5 days after initiation of treatment. High-dose males sang to females significantly less often than males in the other two groups. Low-dose males showed fewer high-intensity courtship displays in which males dance towards females as they sing. These effects on courtship singing were not seen at day 10, though other behavioral effects were seen at this time. Male beak wipes, rocks, following females and female withdrawals from males were also affected by drug treatment. General activity in the home cage was decreased by day 11. These data demonstrate that singing and several other female-directed behaviors are sensitive to perturbations in DA receptor function.

Brief alteration in dopaminergic function during development causes deficits in adult reproductive behavior.

Our previous research revealed dramatic increases in dopaminergic function in vocal control and auditory nuclei in male zebra finches during the period of song learning. Such increases were not seen in the hypothalamic areas examined. In the current study, we manipulated dopamine receptor function during this period to determine how this might affect later singing behavior. Males were implanted with osmotic minipumps providing 0, 0.5, or 5 microg/g/day of the mixed D1/D2 dopamine receptor antagonist cis-flupenthixol from day 45 until day 57. At approximately 86 days of age, males were given subcutaneous silastic implants containing a maintenance dose of androgen, in case antagonist treatment interfered with adult androgen secretion. One week later, they began a series of three weekly tests to determine if this early treatment affected courtship singing. Males treated with the low dose of cis-flupenthixol showed profound decrements in courtship singing and copulatory behavior. Unlike saline-treated controls, low-dose males sang to females infrequently. High-intensity courtship displays in which males dance towards females while singing were most affected. Despite their decreased courtship singing, low-dose males were interested in females. They approached females as frequently as males in the other two groups, but antagonist-treated males were less likely to follow females if they moved. Low-dose males also attempted to mount females significantly less often than high-dose males. High-dose males groomed significantly less frequently than males in the other two groups. Thus, brief early treatment with cis-flupenthixol had profound and long-lasting effects on female-directed singing and on copulatory behavior, despite androgen treatment.

Hormonal modulation of singing: hormonal modulation of the songbird brain and singing behavior.

During the past three decades research on the hormonal control of singing has fundamentally altered our basic concepts about how hormones modulate brain function and activate behavior. Exciting discoveries first documented in songbird brains have since been documented in a wide variety of vertebrate species, including humans. Circulating hormones organize sexual dimorphisms in brain structure during development, activate changes in brain structure during adulthood, and modulate the addition of new neurons in the adult brain. The brain has proved to be the primary source of estrogens in general circulation in adult male finches. Studies of the hormonal modulation of singing are complicated by multiple sites of hormone production, multiple sites of hormone action, hormone metabolism by different tissues, the involvement of a variety of hormones, and the effects of social context. This chapter provides a brief review of these topics, as well as a brief overview of techniques used to study endocrine mechanisms controlling behavior.

Learning from bird brains: how the study of songbird brains revolutionized neuroscience.

During the past 30 years, songbirds have become a popular model for neuroscience research. The author reviews three fundamental discoveries that have revolutionized the field and changed the way we understand the structure and function of the brain.

Vasotocin treatment inhibits courtship in male zebra finches; concomitant androgen treatment inhibits this effect.

Zebra finches evolved in arid areas of Australia. Their reproduction is stimulated by water availability, which is unpredictable. Cheng (Poult. Sci. Rev. 5 (1993) 37) hypothesized that the primary mechanism controlling reproduction in species relying on unpredictable cues should be inhibitory. The onset of stimulatory environmental conditions terminates the inhibition, allowing rapid initiation of reproduction. As the primary hormone regulating water balance in birds, arginine vasotocin (AVT) appears a likely candidate to modulate reproduction in finches. Drought conditions cause sustained AVT release, which in other species inhibits androgen production. To determine whether increased AVT inhibits reproductive behavior, intact males were tested with females and divided into three groups matched for courtship behavior. Osmotic minipumps containing (a) saline, (b) 264 ng AVT, or (c) 1320 ng AVT in saline were implanted subcutaneously and males tested 48 h later. AVT-treated males socialized with females, but the high dose significantly reduced singing and courtship displays. To determine whether AVT acted by depressing androgen secretion, additional males were given subcutaneous androgen implants and divided into two groups matched for courtship behavior. Males were then implanted with minipumps containing (a) saline or (b) the high AVT dose. Males treated with AVT plus androgen showed no deficits in courtship behavior. These data suggest that AVT secretion during periods of drought may inhibit reproduction by inhibiting androgen production. Inhibition of reproductive behavior by AVT may be a more general phenomenon. Large quantities of AVT or, in mammals the closely-related peptide vasopressin (VP), are released when animals are stressed, and high levels of AVT/VP may inhibit reproductive behavior. The extremely short half-life of these peptides means that once proximal factors become more favorable, the gonads should rapidly be released from the peptides' inhibitory actions.