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Understanding how social and affective behavioral states are controlled by neural circuits is a fundamental challenge in neurobiology. Despite increasing understanding of central circuits governing prosocial and agonistic interactions, how bodily autonomic processes regulate these behaviors is less resolved. Thermoregulation is vital for maintaining homeostasis, but also associated with cognitive, physical, affective, and behavioral states. Here, we posit that adjusting body temperature may be integral to the appropriate expression of social behavior and argue that understanding neural links between behavior and thermoregulation is timely. First, changes in behavioral states-including social interaction-often accompany changes in body temperature. Second, recent work has uncovered neural populations controlling both thermoregulatory and social behavioral pathways. We identify additional neural populations that, in separate studies, control social behavior and thermoregulation, and highlight their relevance to human and animal studies. Third, dysregulation of body temperature is linked to human neuropsychiatric disorders. Although body temperature is a "hidden state" in many neurobiological studies, it likely plays an underappreciated role in regulating social and affective states., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes, can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and interferon-gamma (IFNγ), each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes, in turn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease, suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.

Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jeffs, Prather and Todd.)

Animals use a variety of complex signaling mechanisms to convey an array of information that can be detected by conspecifics and heterospecifics. Receivers of those signals perceive that information and use it to direct their subsequent actions. Thus, communication such as that which occurs between senders and receivers of vocal communication signals can be a powerful model in which to investigate the neural basis of sensory perception and action initiation that underlie decision-making. In this study, we investigated how female songbirds perceive the quality of acoustic signals (songs) performed by males and use that information to express preference for one song among many possible alternatives. We use behavioral measurement of song preference before and after lesion-induced alteration of activity in an auditory processing area (caudal nidopallium, NC) for which we have previously described its interconnections with other auditory areas and downstream reward pathways. Our findings reveal that inactivating NC does not change a female's ability or willingness to perform behavioral indicators of mate choice, nor does it change their ability to identify the songs of individual males. However, lesioning NC does induce a decrease in the strength of song preference for specific males more than others. That decrease does not result in a complete elimination of preference, as female preferences for specific males are still evident but not as strongly expressed after lesioning of NC. Taken together, these data indicate that NC plays a role in a female's strength of preference in song evaluation and mate choice, and activity in NC is an important facet of mate choice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lawley, Fenn, Person, Huber, Zaharas, Smith, Coulter and Prather.)

Decision making resides at the interface between sensory perception and movement production. Female songbirds in the context of mate choice are an excellent system to define neural circuits through which sensory perception influences production of courtship behaviors. Previous experiments by our group and others have implicated secondary auditory brain sites, including the caudal nidopallium (NC), in mediating behavioral indicators of mate choice. Here, we used anterograde tracer molecules to define projections that emerge from NC in female songbirds, identifying pathways through which NC influences downstream sites implicated in signal processing and decision making. Our results reveal that NC sends projections into the arcopallium, including the ventral intermediate arcopallium (AIV). Previous work revealed that AIV also receives input from another auditory area implicated in song preference and mate choice (caudal mesopallium, CM), suggesting that convergent input from multiple auditory areas may play important roles in initiating mate choice behaviors. In the present results, NC projects to an area implicated in postural and locomotory control (dorsal arcopallium, Ad), suggesting that NC may play a role in directing those forms of copulatory behavior. NC projections also systematically avoid a vocal motor region of the arcopallium that is innervated by CM (robust nucleus of the arcopallium). These results suggest a model in which both NC and CM project to arcopallial pathways implicated in behavioral motivation. These brain regions may exert different influences on pathways through which auditory information can direct different facets of behavioral responses to information detected in those auditory signals., (© 2022 Wiley Periodicals LLC.)

Birdsong has long been a subject of extensive research in the fields of ethology as well as neuroscience. Neural and behavioral mechanisms underlying song acquisition and production in male songbirds are particularly well studied, mainly because birdsong shares some important features with human speech such as critical dependence on vocal learning. However, birdsong, like human speech, primarily functions as communication signals. The mechanisms of song perception and recognition should also be investigated to attain a deeper understanding of the nature of complex vocal signals. Although relatively less attention has been paid to song receivers compared to signalers, recent studies on female songbirds have begun to reveal the neural basis of song preference. Moreover, there are other studies of song preference in juvenile birds which suggest possible functions of preference in social context including the sensory phase of song learning. Understanding the behavioral and neural mechanisms underlying the formation, maintenance, expression, and alteration of such song preference in birds will potentially give insight into the mechanisms of speech communication in humans. To pursue this line of research, however, it is necessary to understand current methodological challenges in defining and measuring song preference. In addition, consideration of ultimate questions can also be important for laboratory researchers in designing experiments and interpreting results. Here we summarize the current understanding of song preference in female and juvenile songbirds in the context of Tinbergen's four questions, incorporating results ranging from ethological field research to the latest neuroscience findings. We also discuss problems and remaining questions in this field and suggest some possible solutions and future directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fujii, Coulter, Lawley, Prather and Okanoya.)

Depression is an umbrella term used to describe a mood disorder with a broad spectrum of symptoms including a persistent feeling of sadness, loss of interest, and deficits in social behavior. Epigenetic research bridges the environmental and genetic landscape and has the potential to exponentially improve our understanding of such a complex disorder. Depression is also a sexually dimorphic disorder and variations exist within epigenetic modification sites between sexes. These sex-specific mediators may impact behavioral symptomology and could serve as therapeutic targets for treatments to improve behavioral deficits. This mini review will focus on the social behavior perspective of depression and specifically explore the sexually different epigenetic modifications on depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cahill, Poelker-Wells, Prather and Li.)

Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully understood. Strong evidence for a bidirectional relationship between circadian function and pain has been revealed through inflammatory and immune studies as well as neuropathic ones. However, one limitation of many of these studies is a focus on only a few molecules or cell types, often within only one region of the brain or spinal cord, rather than systems-level interactions. To address this, our review will examine the circadian system as a whole, from the intracellular genetic machinery that controls its timing mechanism to its input and output circuits, and how chronic pain, whether inflammatory or neuropathic, may mediate or be driven by changes in these processes. We will investigate how rhythms of circadian clock gene expression and behavior, immune cells, cytokines, chemokines, intracellular signaling, and glial cells affect and are affected by chronic pain in animal models and human pathologies. We will also discuss key areas in both circadian rhythms and chronic pain that are sexually dimorphic. Understanding the overlapping mechanisms and complex interplay between pain and circadian mediators, the various nuclei they affect, and how they differ between sexes, will be crucial to move forward in developing treatments for chronic pain and for determining how and when they will achieve their maximum efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Warfield, Prather and Todd.)

Female songbirds use male song to discriminate among individuals and evaluate their quality as potential mates. Previous behavioral experiments in many species, including the species studied here, have shown that females will solicit copulation in response to song even if no male is present. Those data demonstrate that female mate choice is closely tied to song features, but they leave open the question of which song parameters are most influential in female mate selection. We sought to identify features of male song that are salient for mate choice in female Bengalese finches. Using a novel experimental approach, we simultaneously tested the possible influence of specific notes or note transitions, the number of different note types in the male's repertoire, the complexity of note content and note sequence, and the stereotypy of note content and note sequence. In additional experiments, we also tested the influence of the pitch and tempo of note production. Our results demonstrate that females generally preferred songs containing increased tempo in the context of species-typical frequency bandwidth, consistent with the idea that females prefer songs that are especially challenging to produce. Female preference for song features that pose a neuromuscular challenge has also been reported in other species. Our data extend those observations into a species that thrives in a laboratory setting and is commonly used in studies of the neural basis of behavior. These results provide an excellent new model system in which to study female preference and the neural mechanisms that underlie signal evaluation and mate choice., Competing Interests: The authors have declared that no competing interests exist.

Acoustic communication signals are typically generated to influence the behavior of conspecific receivers. In songbirds, for instance, such cues are routinely used by males to influence the behavior of females and rival males. There is remarkable diversity in vocalizations across songbird species, and the mechanisms of vocal production have been studied extensively, yet there has been comparatively little emphasis on how the receiver perceives those signals and uses that information to direct subsequent actions. Here, we emphasize the receiver as an active participant in the communication process. The roles of sender and receiver can alternate between individuals, resulting in an emergent feedback loop that governs the behavior of both. We describe three lines of research that are beginning to reveal the neural mechanisms that underlie the reciprocal exchange of information in communication. These lines of research focus on the perception of the repertoire of songbird vocalizations, evaluation of vocalizations in mate choice, and the coordination of duet singing., (© 2019 S. Karger AG, Basel.)

Female songbirds use male song as an indicator of fitness and use that information to select their mate. Investigations of the female auditory system have provided evidence that the neurons within the caudal mesopallium (CM) are involved in the processing of songs that a female finds attractive, however, it is not clear how CM may exert its influence on behavioral indicators of mate choice. In the present study, anterograde tracing revealed the efferent connections of the female songbird CM. The results demonstrate connections to other auditory regions previously described in males, as well as novel connections to brain regions implicated in motor control. As in males, CM neurons in females project robustly to the lateral and medial extents of the caudal nidopallium, and to the ventral intermediate arcopallium. In a novel finding that is not present in males, CM neurons also project to the robust nucleus of the arcopallium and to the caudal striatum. Calling behavior and the expression of copulation solicitation displays are key indicators of female mate choice, and the projections found here bridge critical gaps necessary to understand how auditory perception can influence circuits related to the expression of those affiliative behaviors in female songbirds., (© 2018 Wiley Periodicals, Inc.)

In humans and other animals, behavioural variation in learning has been associated with variation in neural features like morphology and myelination. By contrast, it is essentially unknown whether cognitive performance scales with electrophysiological properties of individual neurons. Birdsong learning offers a rich system to investigate this topic as song acquisition is similar to human language learning. Here, we address the interface between behavioural learning and neurophysiology in a cohort of wild-caught, hand-reared songbirds (swamp sparrows, Melospiza georgiana). We report the discovery in the forebrain HVC of sensorimotor 'bridge' neurons that simultaneously and selectively represent two critical learning-related schemas: the bird's own song, and the specific tutor model from which that song was copied. Furthermore, the prevalence and response properties of bridge neurons correlate with learning ability - males that copied tutor songs more accurately had more bridge neurons. Our results are consistent with the hypothesis that accurate imitative learning depends on a successful bridge, within single cortical neurons, between the representation of learning models and their sensorimotor copies. Whether such bridge neurons are a necessary mechanism for accurate learning or an outcome of learning accuracy is unknown at this stage, but can now be addressed in future developmental studies.

Language as a computational cognitive mechanism appears to be unique to the human species. However, there are remarkable behavioral similarities between song learning in songbirds and speech acquisition in human infants that are absent in non-human primates. Here we review important neural parallels between birdsong and speech. In both cases there are separate but continually interacting neural networks that underlie vocal production, sensorimotor learning, and auditory perception and memory. As in the case of human speech, neural activity related to birdsong learning is lateralized, and mirror neurons linking perception and performance may contribute to sensorimotor learning. In songbirds that are learning their songs, there is continual interaction between secondary auditory regions and sensorimotor regions, similar to the interaction between Wernicke's and Broca's areas in human infants acquiring speech and language. Taken together, song learning in birds and speech acquisition in humans may provide useful insights into the evolution and mechanisms of auditory-vocal learning., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sensorimotor integration is the process through which the nervous system creates a link between motor commands and associated sensory feedback. This process allows for the acquisition and refinement of many behaviors, including learned communication behaviors such as speech and birdsong. Consequently, it is important to understand fundamental mechanisms of sensorimotor integration, and comparative analyses of this process can provide vital insight. Songbirds offer a powerful comparative model system to study how the nervous system links motor and sensory information for learning and control. This is because the acquisition, maintenance, and control of birdsong critically depend on sensory feedback. Furthermore, there is an incredible diversity of song organizations across songbird species, ranging from songs with simple, stereotyped sequences to songs with complex sequencing of vocal gestures, as well as a wide diversity of song repertoire sizes. Despite this diversity, the neural circuitry for song learning, control, and maintenance remains highly similar across species. Here, we highlight the utility of songbirds for the analysis of sensorimotor integration and the insights about mechanisms of sensorimotor integration gained by comparing different songbird species. Key conclusions from this comparative analysis are that variation in song sequence complexity seems to covary with the strength of feedback signals in sensorimotor circuits and that sensorimotor circuits contain distinct representations of elements in the vocal repertoire, possibly enabling evolutionary variation in repertoire sizes. We conclude our review by highlighting important areas of research that could benefit from increased comparative focus, with particular emphasis on the integration of new technologies., (Copyright © 2017 the American Physiological Society.)

A recent study demonstrates how acute neural circuit manipulations can lead to overestimations of circuit function, while chronic manipulations can reveal compensatory modes of plasticity that restore behavior., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Songbirds are widely used in studies of the neurobiology underlying learning, memory and performance of the sounds used in vocal communication. Development and activity of neurons in many brain sites implicated in those behaviors are closely related to levels of circulating testosterone. Approaches to understand the effects of testosterone in songbirds are presently limited to testosterone implants, which elevate testosterone levels to supraphysiological values, or castration, which eliminates gonadal production of testosterone. Previous studies in mammals indicate that GnRH agonists may be an effective tool to reduce testosterone within that range of extremes and without invasive surgery. To evaluate the effectiveness of the GnRH agonist Deslorelin as a tool to modulate levels of testosterone in songbirds, we recorded the effects of Deslorelin in adult male zebra finches. We recorded songs, body mass and blood testosterone levels pre-treatment, then we gave each bird a small subcutaneous implant of Deslorelin. We measured blood plasma testosterone levels weekly and recorded song behavior and gross morphology of brain, testes and heart at the end of each experiment. Testosterone levels were reduced at the 5mg/kg dose, and the very slight song changes we observed at that dose were like those reported for castrated zebra finches. As expected, there were no changes in the number of cells in androgen-sensitive brain structures. Suppression of testosterone at the 5mg/kg dose was reversible through implant removal. Thus, Deslorelin is a new tool to transiently suppress testosterone levels without the invasiveness and undesirable aftereffects of surgical castration., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Male songbirds use song to advertise their attractiveness as potential mates, and the properties of those songs have a powerful influence on female mate preferences. One idea is that males may exert themselves maximally in each song performance, consistent with female evaluation and formation of mate preferences being the primary contributors to mate choice. Alternatively, males may modulate their song behaviour to different degrees in the presence of different females, consistent with both male and female mate preferences contributing to mutual mate choice. Here we consider whether male Bengalese finches, Lonchura striata domestica , express mate preferences at the level of individual females, and whether those preferences are manifest as changes in song behaviour that are sufficient to influence female mate choice. We tested this idea by recording songs performed by individual unmated males during a series of 1 h interactions with each of many unmated females. Across recording sessions, males systematically varied both the quantity and the quality of the songs that they performed to different females. Males also varied their song properties throughout the course of each interaction, and behavioural tests using female birds revealed that songs performed at the onset of each interaction were significantly more attractive than songs performed by the same male later during the same interaction. This demonstration of context-specific variation in the properties of male reproductive signals and a role for that variation in shaping female mate preference reveals that male mate preferences play an important role in mutual mate choice in this species. Because these birds thrive so well in the laboratory and are so amenable to observation and experimentation across generations, these results yield a new model system that may prove especially advantageous in disentangling the role of male and female mate preferences in shaping mutual mate choice and its long-term benefits or consequences.

In the process of mate selection by female songbirds, male suitors advertise their quality through reproductive displays in which song plays an important role. Females evaluate the quality of each signal and the associated male, and the results of that evaluation guide expression of selective courtship displays. Some studies reveal broad agreement among females in their preferences for specific signal characteristics, indicating that those features are especially salient in female mate choice. Other studies reveal that females differ in their preference for specific characteristics, indicating that in those cases female evaluation of signal quality is influenced by factors other than simply the physical properties of the signal. Thus, both the physical properties of male signals and specific traits of female signal evaluation can impact female mate choice. Here, we characterized the mate preferences of female Bengalese finches. We found that calls and copulation solicitation displays are equally reliable indicators of female preference. In response to songs from an array of males, each female expressed an individual-specific song preference, and those preferences were consistent across tests spanning many months. Across a population of females, songs of some males were more commonly preferred than others, and females preferred female-directed songs more than undirected songs, suggesting that some song features are broadly attractive. Preferences were indistinguishable for females that did or did not have social experience with the singers, indicating that female preference is strongly directed by song features rather than experiences associated with the singer. Analysis of song properties revealed several candidate parameters that may influence female evaluation. In an initial investigation of those parameters, females could be very selective for one song feature yet not selective for another. Therefore, multiple song parameters are evaluated independently. Together these findings reveal the nature of signal evaluation and mate choice in this species.

Learning and maintaining the sounds we use in vocal communication require accurate perception of the sounds we hear performed by others and feedback-dependent imitation of those sounds to produce our own vocalizations. Understanding how the central nervous system integrates auditory and vocal-motor information to enable communication is a fundamental goal of systems neuroscience, and insights into the mechanisms of those processes will profoundly enhance clinical therapies for communication disorders. Gaining the high-resolution insight necessary to define the circuits and cellular mechanisms underlying human vocal communication is presently impractical. Songbirds are the best animal model of human speech, and this review highlights recent insights into the neural basis of auditory perception and feedback-dependent imitation in those animals. Neural correlates of song perception are present in auditory areas, and those correlates are preserved in the auditory responses of downstream neurons that are also active when the bird sings. Initial tests indicate that singing-related activity in those downstream neurons is associated with vocal-motor performance as opposed to the bird simply hearing itself sing. Therefore, action potentials related to auditory perception and action potentials related to vocal performance are co-localized in individual neurons. Conceptual models of song learning involve comparison of vocal commands and the associated auditory feedback to compute an error signal that is used to guide refinement of subsequent song performances, yet the sites of that comparison remain unknown. Convergence of sensory and motor activity onto individual neurons points to a possible mechanism through which auditory and vocal-motor signals may be linked to enable learning and maintenance of the sounds used in vocal communication. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives"., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Songbirds have emerged as attractive model systems in many areas of biological research. Notably, songbirds are used in studies of the neurobiological and neuroendocrine mechanisms that shape vocal communication, and zebra finches (Taeniopygia guttata) are the most commonly studied species. In these studies, some form of chemical restraint is often needed to facilitate procedures and to minimize the risk of injury during handling. To determine the minimum dose of the benzodiazepine diazepam that is adequate to achieve deep sedation across individual birds, a low dose (5 mg/kg) and a high dose (10 mg/kg) was administered intramuscularly to 20 zebra finches. Results showed that a 10 mg/kg dose of diazepam resulted in deep sedation, defined by dorsal recumbency, which was achieved in minutes and lasted for several hours. Sedation was induced without complication, because no birds displayed signs of distress during sedation or lethargy after recovery, and was adequate to permit minimally invasive surgical procedures. In addition, the duration of sedation was dose dependent, which provides additional information for researchers who seek to match the depth of sedation to their experimental requirements. Finally, complete recovery from the deeply sedated state was induced by a 0.3 mg/kg dose of the antagonist flumazenil, which enabled birds to more rapidly resume homeostatic behaviors to promote well-being and survival. Together, these results indicate that diazepam is a safe and reliable sedative for use in zebra finches and support specific recommendations to achieve rapid and reliable sedation and recovery.

Both sensory and motor mechanisms can constrain behavioral performance. Sensory mechanisms may be especially important for constraining behaviors that depend on experience, such as learned birdsongs. Swamp sparrows learn to sing by imitating the song of a tutor, but sparrows fail to accurately imitate artificial tutor songs with abnormally accelerated trills, instead singing brief and rapid trills interrupted by silent gaps. This "broken syntax" has been proposed to arise from vocal-motor limitations. Here we consider whether sensory limitations exist that could also contribute to broken syntax. We tested this idea by recording auditory-evoked activity of sensorimotor neurons in the swamp sparrow's brain that are known to be important for the learning, performance and perception of song. In freely behaving adult sparrows that sang songs with normal syntax, neurons were detected that exhibited precisely time-locked activity to each repetition of the syllable in a trill when presented at a natural rate. Those cells failed to faithfully follow syllables presented at an accelerated rate, however, and their failure to respond to consecutive syllables increased as a function of trill rate. This "flickering" auditory representation in animals performing normal syntax reveals a central constraint on the sensory processing of rapid trills. Furthermore, because these neurons are implicated in both song learning and perception, and because auditory flickering began to occur at accelerated trill rates previously associated with the emergence of broken song syntax, these sensory constraints may contribute to the emergence of broken syntax.

Sensorimotor functions are restored by peripheral nerve regeneration with greater success following injuries that crush rather than sever the nerve. Better recovery following nerve crush is commonly attributed to superior reconnection of regenerating axons with their original peripheral targets. The present study was designed to estimate the fraction of stretch reflex recovery attributable to functional recovery of regenerated spindle afferents. Recovery of the spindle afferent population was estimated from excitatory postsynaptic potentials evoked by muscle stretch (strEPSPs) in motoneurons. These events were measured in cats that were anaesthetized, so that recovery of spindle afferent function, including both muscle stretch encoding and monosynaptic transmission, could be separated from other factors that act centrally to influence muscle stretch-evoked excitation of motoneurons. Recovery of strEPSPs to 70% of normal specified the extent of overall functional recovery by the population spindle afferents that regained responsiveness to muscle stretch. In separate studies, we examined recovery of the stretch reflex in decerebrate cats, and found that it recovered to supranormal levels after nerve crush. The substantial disparity in recovery between strEPSPs and stretch reflex led us to conclude that factors in addition to recovery of spindle afferents make a large contribution in restoring the stretch reflex following nerve crush.

Juveniles sometimes learn behaviors that they cease to express as adults. Whether the adult brain retains a record of experiences associated with behaviors performed transiently during development remains unclear. We addressed this issue by studying neural representations of song in swamp sparrows, a species in which juveniles learn and practice many more songs than they retain in their adult vocal repertoire. We exposed juvenile swamp sparrows to a suite of tutor songs and confirmed that, although many tutor songs were imitated during development, not all copied songs were retained into adulthood. We then recorded extracellularly in the sensorimotor nucleus HVC in anesthetized sparrows to assess neuronal responsiveness to songs in the adult repertoire, tutor songs, and novel songs. Individual HVC neurons almost always responded to songs in the adult repertoire and commonly responded even more strongly to a tutor song. Effective tutor songs were not simply those that were acoustically similar to songs in the adult repertoire. Moreover, the strength of tutor song responses was unrelated to the number of times that the bird sang copies of those songs in juvenile or adult life. Notably, several neurons responded most strongly to a tutor song performed only rarely and transiently during juvenile life, or even to a tutor song for which we could find no evidence of ever having been copied. Thus, HVC neurons representing songs in the adult repertoire also appear to retain a lasting record of certain tutor songs, including those imitated only transiently.

The division of continuously variable acoustic signals into discrete perceptual categories is a fundamental feature of vocal communication, including human speech. Despite the importance of categorical perception to learned vocal communication, the neural correlates underlying this phenomenon await identification. We found that individual sensorimotor neurons in freely behaving swamp sparrows expressed categorical auditory responses to changes in note duration, a learned feature of their songs, and that the neural response boundary accurately predicted the categorical perceptual boundary measured in field studies of the same sparrow population. Furthermore, swamp sparrow populations that learned different song dialects showed different categorical perceptual boundaries that were consistent with the boundary being learned. Our results extend the analysis of the neural basis of perceptual categorization into the realm of vocal communication and advance the learned vocalizations of songbirds as a model for investigating how experience shapes categorical perception and the activity of categorically responsive neurons.

Songbirds learn to sing by memorizing a tutor song that they then vocally mimic using auditory feedback. This developmental sequence suggests that brain areas that encode auditory memories communicate with brain areas for learned vocal control. In the songbird, the secondary auditory telencephalic region caudal mesopallium (CM) contains neurons that encode aspects of auditory experience. We investigated whether CM is an important source of auditory input to two sensorimotor structures implicated in singing, the telencephalic song nucleus interface (NIf) and HVC. We used reversible inactivation methods to show that activity in CM is necessary for much of the auditory-evoked activity that can be detected in NIf and HVC of anesthetized adult male zebra finches. Furthermore, extracellular and intracellular recordings along with spike-triggered averaging methods indicate that auditory selectivity for the bird's own song is enhanced between CM and NIf. We used lentiviral-mediated tracing methods to confirm that CM neurons directly innervate NIf. To our surprise, these tracing studies also revealed a direct projection from CM to HVC. We combined irreversible lesions of NIf with reversible inactivation of CM to establish that CM supplies a direct source of auditory drive to HVC. Finally, using chronic recording methods, we found that CM neurons are active in response to song playback and during singing, indicating their potential importance to song perception and processing of auditory feedback. These results establish the functional synaptic linkage between sites of auditory and vocal learning and may identify an important substrate for learned vocal communication.

Brain mechanisms for communication must establish a correspondence between sensory and motor codes used to represent the signal. One idea is that this correspondence is established at the level of single neurons that are active when the individual performs a particular gesture or observes a similar gesture performed by another individual. Although neurons that display a precise auditory-vocal correspondence could facilitate vocal communication, they have yet to be identified. Here we report that a certain class of neurons in the swamp sparrow forebrain displays a precise auditory-vocal correspondence. We show that these neurons respond in a temporally precise fashion to auditory presentation of certain note sequences in this songbird's repertoire and to similar note sequences in other birds' songs. These neurons display nearly identical patterns of activity when the bird sings the same sequence, and disrupting auditory feedback does not alter this singing-related activity, indicating it is motor in nature. Furthermore, these neurons innervate striatal structures important for song learning, raising the possibility that singing-related activity in these cells is compared to auditory feedback to guide vocal learning.

Long after a cut peripheral nerve reinnervates muscle and restores force production in adult cats, the muscle does not respond reflexively to stretch. Motivated by the likelihood that stretch areflexia is related to problems with sensing and controlling limb position after peripheral neuropathies, we sought to determine the underlying mechanism. Electrophysiological and morphological measurements were made in anesthetized rats having one of the nerves to the triceps surae muscles either untreated or cut and immediately rejoined surgically many months earlier. First, it was established that reinnervated muscles failed to generate stretch reflexes, extending observations of areflexia to a second species. Next, multiple elements in the sensorimotor circuit of the stretch reflex were examined in both the PNS and CNS. Encoding of muscle stretch by regenerated proprioceptive afferents was remarkably similar to normal, although we observed some expected abnormalities, e.g., increased length threshold. However, the robust stretch-evoked sensory response that arrived concurrently at the CNS in multiple proprioceptive afferents produced synaptic responses that were either smaller than normal or undetectable. Muscle stretch failed to evoke detectable synaptic responses in 13 of 22 motoneurons, although electrical stimulation generated monosynaptic excitatory postsynaptic potentials that were indistinguishable from normal. The ineffectiveness of muscle stretch was not attributable therefore to dysfunction at synapses made between regenerated Ia afferents and motoneurons. Among multiple candidate mechanisms, we suggest that centrally controlled neural circuits may actively suppress the sensory information encoded by regenerated proprioceptive afferents to prevent recovery of the stretch reflex.

Synaptic interactions between telencephalic neurons innervating descending motor or basal ganglia pathways are essential in the learning, planning, and execution of complex movements. Synaptic interactions within the songbird telencephalic nucleus HVC are implicated in motor and auditory activity associated with learned vocalizations. HVC contains projection neurons (PNs) (HVC(RA)) that innervate song premotor areas, other PNs (HVC(X)) that innervate a basal ganglia pathway necessary for vocal plasticity, and interneurons (HVC(INT)). During singing, HVC(RA) fire in temporally sparse bursts, possibly because of HVC(INT)-HVC(RA) interactions, and a corollary discharge can be detected in the basal ganglia pathway, likely because of synaptic transmission from HVC(RA) to HVC(X) cells. During song playback, local interactions, including inhibition onto HVC(X) cells, shape highly selective responses that distinguish HVC from its auditory afferents. To better understand the synaptic substrate for the motor and auditory properties of HVC, we made intracellular recordings from pairs of HVC neurons in adult male zebra finch brain slices and used spike-triggered averages to assess synaptic connectivity. A major synaptic interaction between the PNs was a disynaptic inhibition from HVC(RA) to HVC(X), which could link song motor signals in the two outputs of HVC and account for some of the song playback-evoked inhibition in HVC(X) cells. Furthermore, single interneurons made divergent connections onto PNs of both types, and either PN type could form reciprocal connections with interneurons. In these two regards, the synaptic architecture of HVC resembles that described in some pattern-generating networks, underscoring features likely to be important to singing and song learning.

Songbirds are extraordinary vocalists and sensitive listeners, singing to communicate identity, engage other birds in acoustical combat, and attract mates. These processes involve auditory plasticity in that birds rapidly learn to discriminate novel from familiar songs. Songbirds also are one of the few non-human animals that use auditory feedback to learn their vocalizations, thus auditory -- vocal interactions are likely to be important to vocal learning. Recent advances strengthen the connection between song recognition and processing of birdsong in the auditory telencephalon. New insights also have emerged into the mechanisms underlying the 'gating' of auditory responses and the emergence of highly selective responses, two processes that could facilitate auditory feedback important to song learning.

The aim of this study was to investigate whether activation of spinal motoneurons by sensory afferents of the caudal cutaneous sural (CCS) nerve evokes an atypical motor control scheme. In this scheme, motor units that contract fast and forcefully are driven by CCS afferents to fire faster than motor units that contract more slowly and weakly. This is the opposite of the scheme described by the size principle. Earlier studies from this lab do not support the atypical scheme and instead demonstrate that both CCS and muscle stretch recruit motor units according to the size principle. The latter finding may indicate that CCS and muscle-stretch inputs have similar functional organizations or that comparison of recruitment sequence was simply unable to resolve a difference. In the present experiments, we examine this issue using rate modulation as a more sensitive index of motoneuron activation than recruitment. Quantification of the firing output generated by these two inputs in the same pairs of motoneurons enabled direct comparison of the functional arrangements of CCS versus muscle-stretch inputs across the pool of medial gastrocnemius (MG) motoneurons. No systematic difference was observed in the rate modulation produced by CCS versus muscle-stretch inputs for 35 pairs of MG motoneurons. For the subset of 24 motoneuron pairs exhibiting linear co-modulation of firing rate (r > 0.5) in response to both CCS and muscle inputs, the slopes of the regression lines were statistically indistinguishable between the two inputs. For individual motoneuron pairs, small differences in slope between inputs were not related to differences in conduction velocity (CV), recruitment order, or, for a small sample, differences in motor unit force. We conclude that an atypical motor control scheme involving selective activation of typically less excitable motoneurons, if it does occur during normal movement, is not an obligatory consequence of activation by sural nerve afferents. On average and for both muscle-stretch and skin-pinch inputs, the motoneuron with the faster CV in the pair tended to be driven to fire at slightly but significantly faster firing rates. Computer simulations based in part on frequency-current relations measured directly from motoneurons revealed that properties intrinsic to motoneurons are sufficient to account for the higher firing rates of the faster CV motoneuron in a pair.

This study provides the first test in vivo of the hypothesis that group Ia muscle-stretch afferents aid in preventing reversals in the orderly recruitment of motoneurons. This hypothesis was tested by studying recruitment of motoneurons deprived of homonymous afferent input. Recruitment order was measured in decerebrate, paralyzed cats from dual intra-axonal records obtained simultaneously from pairs of medial gastrocnemius (MG) motoneurons. Pairs of MG motor axons were recruited in eight separate trials of the reflex discharge evoked by stimulation of the caudal cutaneous sural (CCS) nerve. Some reports suggest that reflex recruitment by this cutaneous input should bias recruitment against order by the size principle in which the axon with the slower conduction velocity (CV) in a pair is recruited to fire before the faster CV axon. Recruitment was studied in three groups of cats: ones with the MG nerve intact and untreated (UNTREATED); ones with the MG nerve cut (CUT); and ones with the MG nerve cut and bathed at its proximal end in lidocaine solution (CUT+). The failure of electrical stimulation to initiate a dorsal root volley and the absence of action potentials in MG afferents demonstrated the effective elimination of afferent feedback in the CUT+ group. Recruitment order by the size principle predominated and was not statistically distinguishable among the three groups. The percentage of pairs recruited in reverse order of the size principle was actually smaller in the CUT+ group (6%) than in CUT (15%) or UNTREATED (19%) groups. Thus homonymous afferent feedback is not necessary to prevent recruitment reversal. However, removing homonymous afferent input did result in the expression of inconsistency in order, i.e., switches in recruitment sequence from one trial to the next, for more axon pairs in the CUT+ group (33%) than for the other groups combined (13%). Increased inconsistency in the absence of increased reversal of recruitment order was approximated in computer simulations by increasing time-varying fluctuations in synaptic drive to motoneurons and could not be reproduced simply by deleting synaptic current from group Ia homonymous afferents, regardless of how that current was distributed to the motoneurons. These findings reject the hypothesis that synaptic input from homonymous group Ia afferents is necessary to prevent recruitment reversals, and they are consistent with the assertion that recruitment order is established predominantly by properties intrinsic to motoneurons.

The aim of this study was to measure the effects of synaptic input on motoneuron firing rate in an unanesthetized cat preparation, where activation of voltage-sensitive dendritic conductances may influence synaptic integration and repetitive firing. In anesthetized cats, the change in firing rate produced by a steady synaptic input is approximately equal to the product of the effective synaptic current measured at the resting potential (I(N)) and the slope of the linear relation between somatically injected current and motoneuron discharge rate (f-I slope). However, previous studies in the unanesthetized decerebrate cat indicate that firing rate modulation may be strongly influenced by voltage-dependent dendritic conductances. To quantify the effects of these conductances on motoneuron firing behavior, we injected suprathreshold current steps into medial gastrocnemius motoneurons of decerebrate cats and measured the changes in firing rate produced by superimposed excitatory synaptic input. In the same cells, we measured I(N) and the f-I slope to determine the predicted change in firing rate (Delta F = I(N) * f-I slope). In contrast to previous results in anesthetized cats, synaptically induced changes in motoneuron firing rate were greater-than-predicted. This enhanced effect indicates that additional inward current was present during repetitive firing. This additional inward current amplified the effective synaptic currents produced by two different excitatory sources, group Ia muscle spindle afferents and caudal cutaneous sural nerve afferents. There was a trend toward more prevalent amplification of the Ia input (14/16 cells) than the sural input (11/16 cells). However, in those cells where both inputs were amplified (10/16 cells), amplification was similar in magnitude for each source. When these two synaptic inputs were simultaneously activated, their combined effect was generally very close to the linear sum of their amplified individual effects. Linear summation is also observed in medial gastrocnemius motoneurons of anesthetized cats, where amplification is not present. This similarity suggests that amplification does not disturb the processes of synaptic integration. Linear summation of amplified input was evident for the two segmental inputs studied here. If these phenomena also hold for other synaptic sources, then the presence of active dendritic conductances underlying amplification might enable motoneurons to integrate multiple synaptic inputs and drive motoneuron firing rates throughout the entire physiological range in a relatively simple fashion.

Rat blood and various tissues were analyzed for levels of isosorbide dinitrate (ISDN), an antianginal drug, after the administration of 14C-labeled compound. Unaltered [14C]ISDN was found in all tissues analyzed and in the circulating blood for up to 4 hours after p.o. or i.v. administration. These results clearly show that ISDN is not completely degraded in a single pass through the liver after either route of administration. ISDN concentration (nanograms of ISDN per gram wet weight of tissue) in vascular tissue were significantly greater than other tissues or the blood.