Regulation of vocal precision by noradrenergic modulation of a motor nucleus.

Recent theories of norepinephrine (NE) function suggest that NE modulates the transition between stereotyped, goal-directed behavior and more variable, exploratory behaviors that facilitate learning and adaptation. We provide evidence for context-dependent switching by NE that is analogous to this explore/exploit strategy in the vocal system of the zebra finch (Taeniopygia guttata). Stimulation of the locus coeruleus, the major source of NE in the brain, decreases song trial-to-trial variability, transforming the variable, exploratory "undirected" song into song that resembles the more stereotyped, exploitative "directed" song that males sing to females. This behavioral switch is mediated by NE acting directly on a cortical motor nucleus that integrates inputs from a premotor cortical nucleus and a basal ganglia circuit necessary for vocal motor learning. These findings suggest that NE can act directly on the motor system to influence the transition between exploratory and exploitative behavioral strategies.NEW & NOTEWORTHY Norepinephrine (NE) function is often implicated in regulating arousal levels. Recent theory suggests that the noradrenergic system also regulates the optimization of behavior with respect to reward maximization by controlling a switch between exploration and exploitation of the specific actions that yield greatest utility. We show in the songbird that NE can act directly on a cortical motor area and cause a switch between exploratory and exploitative behavior.

Stress and glucocorticoids impair memory retrieval via ß2-adrenergic, Gi/o-coupled suppression of cAMP signaling.

Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating ß(1)-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, ß(1), and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of ß(2) (but not ß(1))-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and ß(2) agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G(i/o)-coupled receptors. In hippocampal slices, ß(2) signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by ß(1) signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic ß(2) agonists or glucocorticoids. These results demonstrate that the ß(2) receptor can be a critical effector of acute stress, and that ß(1) and ß(2) receptors can have quite distinct roles in CNS signaling and cognition.

What birdsong can teach us about the central noradrenergic system.

Increasing evidence indicates that the noradrenergic system plays a key role in biasing the nervous system towards producing behaviors that help animals adapt to constantly changing environments. Most of the studies investigating noradrenergic function are performed in animals that have a limited repertoire of tractable natural behaviors. Songbirds, in contrast, with their rich set of precisely quantifiable vocal behaviors, provide a unique model system to study the noradrenergic system. An additional advantage of this system is the existence of a well-defined neural circuit, known as the song system, that is necessary for the production, learning and perception of song and can be studied at many different levels. These include the ability to investigate the effect of norepinephrine on synaptic function using brain slices, identifying its influence on singing-related gene expression and monitoring its impact on the activity of single neurons recorded in awake behaving birds. In this review article, we describe the similarities and differences, both anatomical and functional, between the avian and mammalian noradrenergic system and its role in sensory processing, learning, attention and synaptic modulation. We also describe how the noradrenergic system influences motor production, an under-explored aspect of norepinephrine function in mammalian studies. We argue that the richness of behaviors observed in songbirds provides a unique opportunity to study the noradrenergic system in a highly integrative manner that will ultimately provide important insights into the role of this system in normal behavior and disease.

Dopamine binds to alpha(2)-adrenergic receptors in the song control system of zebra finches (Taeniopygia guttata).

A commonly held view is that dopamine exerts its effects via binding to D1- and D2-dopaminergic receptors. However, recent data have emerged supporting the existence of a direct interaction of dopamine with adrenergic but this interaction has been poorly investigated. In this study, the pharmacological basis of possible in vivo interactions between dopamine and alpha(2)-adrenergic receptors was investigated in zebra finches. A binding competition study showed that dopamine displaces the binding of the alpha(2)-adrenergic ligand, [(3)H]RX821002, in the brain. The affinity of dopamine for the adrenergic sites does not differ between the sexes and is 10- to 28-fold lower than that for norepinephrine. To assess the anatomical distribution of this interaction, binding competitions were performed on brain slices incubated in 5nM [(3)H]RX821002 in the absence of any competitor or in the presence of norepinephrine [0.1microM] or dopamine [1microM]. Both norepinephrine and dopamine displaced the binding of the radioligand though to a different extent in most of the regions studied (e.g., area X, the lateral part of the magnocellular nucleus of anterior nidopallium, HVC, arcopallium dorsale, ventral tegmental area and substantia grisea centralis) but not in the robust nucleus of the arcopallium. Together these data provide evidence for a direct interaction between dopamine and adrenergic receptors in songbird brains albeit with regional variation.

Noradrenergic projections to the song control nucleus area X of the medial striatum in male zebra finches (Taeniopygia guttata).

There is considerable functional evidence implicating norepinephrine in modulating activity in the vocal control circuit of songbirds. However, our knowledge of noradrenergic inputs to the song system is incomplete. In this study, cholera toxin subunit B (CTB) injections into area X revealed projections from the noradrenergic nuclei locus coeruleus and subcoeruleus, and injections of biotinylated dextran amines into these noradrenergic nuclei labeled fibers in area X. The nonreciprocity of this connection was demonstrated by the absence of retrogradely labeled cells in area X following injections of CTB into the locus coeruleus. Additionally, we found novel inputs to area X from the nidopallium and arcopallium, the mesencephalic central gray, and the dorsolateralis anterior (DLL) and posterior (DLP) lateralis in the thalamus. Area X can be clearly distinguished from the surrounding medial striatum based on cytoarchitectural and chemical neuroanatomical criteria. We show here that neuromodulatory inputs to area X however, exhibit a considerable degree of overlap with the surrounding area. This finding suggests that regional specificity in neuromodulator action is most likely afforded by a specialization in receptor density and enzyme distribution rather than projections from the synthesizing nuclei. Our results extend current knowledge about noradrenergic projections to specialized nuclei of the song control circuit and provide neuroanatomical evidence for the functional action of norepinephrine-modulating context-dependent ZENK expression in area X. Furthermore, the novel projections to area X from telencephalic and thalamic areas could be new and interesting nodes in the striatopallidothalamic loop spanning the songbird brain.

A role for norepinephrine in the regulation of context-dependent ZENK expression in male zebra finches (Taeniopygia guttata).

Singing drives expression of the immediate-early gene ZENK in a context-dependent manner in certain nuclei within the avian song circuit of male zebra finches (Taeniopygia guttata). ZENK mRNA expression is low when males are engaged in female- or male-directed song, but high during solo song. Neurotransmitter systems like catecholamines with diffuse projections to forebrain regions are good candidates for regulation of such context-dependent brain activity. We investigated whether the noradrenergic system regulates the dramatic switch in ZENK expression across contexts in male zebra finches. We systemically injected a noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and found a marked increase in the resultant ZENK expression in area X of the medial striatum in male zebra finches singing directed song. ZENK protein expression in saline-treated males across different contexts mirrored the pattern of previously reported ZENK mRNA expression. We corroborated DSP-4 specificity via immunohistochemical procedures for tyrosine hydroxylase and dopamine-beta hydroxylase, which revealed decreases in norepinephrine synthesizing nuclei and certain song control nuclei. Based on these results we propose a mechanism by which the noradrenergic system usually downregulates ZENK expression in area X during directed song. By depleting this system we induced a disruption of this regulation and reversion back to the default situation characterized by an increase in motor-driven ZENK expression in the song circuit. These data demonstrate that the noradrenergic system (probably in concert with other modulatory neurotransmitters) plays an important role in the response of the brain to salient events that occur in the context of a natural behavior--singing.

The activation of birdsong by testosterone: multiple sites of action and role of ascending catecholamine projections.

Birdsong is a species-typical stereotypic vocalization produced in the context of reproduction and aggression. Among temperate-zone songbirds, it is produced primarily by males, and its frequency and quality are enhanced by the presence of the gonadal steroid hormone testosterone in the plasma. In the brain, the effects of testosterone on song behavior involve both estrogenic and androgenic metabolites of testosterone that are locally produced and act via their cognate receptors. Androgen, and in some cases estrogen, receptors are present in many specialized forebrain song control nuclei. Testosterone can regulate catecholamine steady-state levels and turnover in these song control regions. Tracing studies combined with immunocytochemistry for tyrosine hydroxylase (a marker of catecholamine synthesis) reveal several catecholamine cell groups that project to forebrain song control nuclei. These brain areas also express the mRNA for either androgen receptors or estrogen receptor alpha, and androgens enhance the expression of tyrosine hydroxylase. Dopaminergic cell groups that project to song nuclei express the protein product of the immediate early gene fos in association with the production of territorial song. Thus, testosterone may be acting on song behavior via these ascending catecholamine cell groups. Chemical lesioning studies suggest that noradrenergic projections to the song system are involved in the latency to produce song and the ability to discriminate conspecific from heterospecific song. The song control circuit may thus be modulated in significant ways via the androgen regulation of forebrain catecholamine systems.