SEARCH

SEARCH BY CITATION

Keywords:

  • Addiction;
  • affective disorders;
  • animal communication;
  • autism;
  • bioacoustic communication;
  • empathy;
  • mood;
  • schizophrenia;
  • ultrasonic vocalizations

Abstract

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments

Mental illness can include impaired abilities to express emotions or respond to the emotions of others. Speech provides a mechanism for expressing emotions, by both what words are spoken and by the melody or intonation of speech (prosody). Through the perception of variations in prosody, an individual can detect changes in another's emotional state. Prosodic features of mouse ultrasonic vocalizations (USVs), indicated by changes in frequency and amplitude, also convey information. Dams retrieve pups that emit separation calls, females approach males emitting solicitous calls, and mice can become fearful of a cue associated with the vocalizations of a distressed conspecific. Because acoustic features of mouse USVs respond to drugs and genetic manipulations that influence reward circuits, USV analysis can be employed to examine how genes influence social motivation, affect regulation, and communication. The purpose of this review is to discuss how genetic and developmental factors influence aspects of the mouse vocal repertoire and how mice respond to the vocalizations of their conspecifics. To generate falsifiable hypotheses about the emotional content of particular calls, this review addresses USV analysis within the framework of affective neuroscience (e.g. measures of motivated behavior such as conditioned place preference tests, brain activity and systemic physiology). Suggested future studies include employment of an expanded array of physiological and statistical approaches to identify the salient acoustic features of mouse vocalizations. We are particularly interested in rearing environments that incorporate sufficient spatial and temporal complexity to familiarize developing mice with a broader array of affective states.

Many of life's enriching experiences occur within a social context, with the ability to share enjoyment, to grasp how another individual feels, or to see the world from the perspective of another. In a variety of developmental disabilities and neurological diseases, these capacities are diminished or lost (Abdi & Sharma 2004, Freeman et al. 2009, Hagerman et al. 1986, Lord et al. 2000, O’Keeffe et al. 2007, Orbelo et al. 2005, Ruby & Decety 2004, Testa et al. 2001). To elucidate how these deficits emerge in development, adulthood or aging, emotional experiences cannot be directly measured. Rather, changes in behaviors are used as a metric to infer changes in emotion. For example, the level of fear experienced by a person cannot be measured but the quiver of a fearful voice can be detected. Scientists can also measure behavioral indications of empathy; how one individual responds to the emotional expressions of another individual. For instance, in response to hearing the quiver in a voice, an individual might feel compassion, fearful, vindicated, frustrated or angry. In turn, these emotions can engender various behavioral responses, such as expression of consoling words, flight from the scene, pursed lips, or a confrontation with the dangerous stimulus. The purpose of this review is to explore how mouse vocalizations convey emotional information, how mice respond to these vocalizations, and how we can infer affective states from changes in the mouse vocal repertoire.

Prosody

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments

Vocalizations provide highly salient cues that can indicate changes in emotion. Emotional information can be provided by what words are spoken (from the meanings of the words themselves). ‘That feels great!’‘You’re making me frustrated’. ‘That dude gives me the creeps'. We know the meaning of these statements and we often express an emotional response to them. But emotions are also expressed by how words are spoken. This quality of speech, which is called ‘prosody’ and is often referred to as intonation, is central to communication. Prosody is measured by variations in the pitch (notes), energy (loudness), and the duration of spoken words and the timing between them.

Prosody can be classified into three functional groups. Grammatical prosody entails changes in emphasis on particular syllables, or changes in pitch, within a sentence that can help us distinguish meanings. For example, applications of stress on one of two syllables in a word can help us to differentiate a dry, treeless ecosystem (des'-ert) from the pleasant plate of food at the end of a meal (des-sert'). An upward trend in pitch through a sentence enables us to discern a question from an assertion. The soup bowl is in the kitchen. The soup bowl is in the kitchen? Pragmatic prosody is used to help us put emphasis on an important idea, sentence or word in a sentence, and thus shows our focus and intentions. For example, enhanced duration and loudness of a particular word can indicate its importance within a sentence. ‘I don't want the brown coat, I want the DOWN coat'. A different function of pragmatic prosody is that it signals the context, roles, and relationships between speakers. People speak to infants in ‘motherese’ or ‘infant-directed talk’ in a voice that they do not use with older children (Fernald 1989). People speak with one tone to their employer and a different tone with their intimate partner. Affective prosody is responsive to internal emotional experiences, such as sadness, anger, fatigue, annoyance, concern, contentment, relief, excitement or victory. For instance, high levels of frequency modulation, in which there are broad variations in the level of pitch, from syllable to syllable, can be associated with excitement. A minimal level of frequency modulation, or monotone, can indicate boredom or fatigue. Prosody is also responsive to social context. Adults talk with old friends and new acquaintances with different vocal patterns. The variability of speech within the context of changes in emotion or social context is referred to as emotional or affective prosody.

Affective prosody and mental disorders

Autistic individuals have been shown to assign stress to the wrong syllables of a word (Baltaxe 1984, Baltaxe & Guthrie 1987, Shriberg et al. 2001) and children with high-functioning autism can have difficulties modulating the pitch and controlling the volume of their speech (Shriberg et al. 2001). Some aspects of autistic speech incorporate all three features of the diagnosis: repetitive behaviors, deficits in the ability to express emotions and deficits in communication. For instance, some children with autism repeat the use of certain sounds, syllables or words, more than typically developing children (Shriberg et al. 2001), or fail to use appropriate patterns of intonation to communicate. Prosody can be monotonic, minimally pitched or energy modulated, or it can be amplified in pitch range or even singsong-like (Amorosa 1992), masking dynamics in emotional status. Autistic language may not be appropriately attuned to context, or ‘machine-like’ (Fine et al. 1991). Overall, speech impairments in autism are generally more prevalent in the expression of pragmatic or affective prosody than grammatical prosody (Shriberg et al. 2001). Individuals with an autism diagnosis can have impairments in the ability to understand the spoken language and gestures of others, even as infants (Golan et al. 2007, Kuhl et al. 2005, Rutherford et al. 2002). The ability to respond to the emotional expressions of others can be deficient among people with autism (Silani et al. 2008, Smith 2009). In this regard, autistic children also show deficits in their abilities to use prosodic cues to disambiguate sentence meaning (Diehl et al. 2008). These deficits can extend to inabilities to interpret intonations that denote liking or disliking (McCann et al. 2007).

Schizophrenia, mania and depression can also be significantly impaired in the ability to comprehend affective prosody, while schizophrenia can additionally feature substantial deficits in the ability to express affective prosody (Murphy & Cutting 1990). Schizophrenia can feature deficits in expressive and receptive prosody (Bach et al. 2009, Leentjens et al. 1998, Leitman et al. 2006), especially in paranoid (Bach et al. 2009) and flat affect (Alpert et al. 2000) schizophrenia. For instance, individuals with flat affect schizophrenia employ normal word patterns to express emotions (frequency of words describing pleasurable or distressful experiences), but they communicate these experiences with less prosodic inflection (Alpert et al. 2000). Like autism disorders, there are many forms of schizophrenia which do not all show deficits in the expressive prosody (Cohen & Docherty 2005, Wan et al. 2008). Receptivity to emotional expressions of others can also be impaired in schizophrenia (Derntl et al. 2009, Fujiwara et al. 2008, Haker & Rossler 2009), particularly in males who are responding to emotions that have negative valence (Bozikas et al. 2006, Pijnenborg et al. 2007, Scholten et al. 2008). In addition to schizophrenia, responsiveness to affective prosody can be impaired in depression (Emerson et al. 1999, Uekermann et al. 2008), multiple sclerosis (Beatty et al. 2003), Parkinson's disease (Benke et al. 1998), alcoholism (Monnot et al. 2001, 2002, Uekermann & Daum 2008, Uekermann et al. 2005) and following exposure to MDMA or ‘ecstasy’ (Yip & Lee 2006).

Mouse vocalizations

To model deficits in expressive and receptive prosody, there must be evidence that features of mouse vocalizations typically associate with specific affective states, such as distress, or reward, or anticipation of reward and whether these features can be sensitive to differences in specific alleles or genetic background. Mice have the capability to vocalize across a broad range of frequencies that extend from as low as the human-audible range (when we hear squeaks) to well into the ultrasound range, above the limit of human hearing [20 000 cycles per second (hertz) = 20 kHz]. Audible squeaks are produced by laboratory mice in stressful and painful situations (Whitney & Nyby 1983), such as during handling and restraint (Whitney 1969), grid-shock test (Winter 1965) or during aggressive encounters (Gourbal et al. 2004, Houseknecht 1968). In reproductive contexts, human-audible squeaks are produced by females when a sexually motivated male is interacting with a non-receptive female (Sales 1972).

Over the last 40 years, mouse vocalizations have been studied mostly within two social contexts: adult male vocalizations emitted in response to the cues of estrous females and vocalizations emitted when pups are separated from the nest. Initial analyses of these calls were limited to rate of call production within a particular bandwidth of frequencies. More recently, analyses include classification of discrete vocalizations based upon their differences in frequency (pitch) and energy (loudness).

Adult male–female interactions

Adult vocalizations have been primarily studied within reproductive contexts. Adult males emit ultrasonic vocalizations (USVs) when exposed to a female partner or to her odor cues (Maggio et al. 1983, Nyby 2001, Whitney & Nyby 1979). During courtship, the male vocalizes and approaches the female (Maggio et al. 1983, Whitney & Nyby 1979). The relationship between male USV production and female behavior suggests that USVs predict mating opportunities rather than aggression. Female responses to these USVs include attenuated aggressive behaviors, approach and more frequent expression of mating postures (Sewell 1969). In a two-compartment choice test, females approach tethered males that are vocalizing vs. males that are surgically rendered incapable of vocalizing. If both males are rendered unable to vocalize, but one of the males is placed next to an ultrasound generator producing 70 kHZ ultrasounds, females prefer to reside in the compartment containing the male with the sound generator (Pomerantz et al. 1983).

During these male–female social interactions, males emit two types of vocalizations (Maggio et al. 1983, Nyby & Whitney 1978, Wang et al. 2008, Whitney & Nyby 1979). One is a highly modulated pure tone with a mean frequency of around 70 kHz and an intensity of 40 dB (Sales & Pye 1974). The second is a pure tone around 40 kHz with an intensity of more than 100 dB. The male emits the 70 kHz calls almost continuously prior to the first mount, while he actively sniffs and investigates the female. After the first mount, the number of calls declines, although during the latter stages of copulatory behavior, the male intermixes both 70 and 40 kHz calls immediately before and between mounting bouts (Nyby 1983, Sales & Pye 1974, White et al. 1998).

The development of digital sound spectrographic analysis of USVs has allowed researchers to expand analyses of mouse vocalizations to include dynamic changes in mean frequency (pitch). Individual calls can then be classified according to changes in dominant frequency, as a function of time. This analytical approach was used to assess USVs of adult males that were elicited by odors of receptive adult females (Holy & Guo 2005). Recordings were collected and calls were classified. For each call, pitch changes were compared for sudden punctuations in pitch that occur within a syllable. This analysis showed distinct clusters of pitch changes, such as upward and downward jumps between comparatively low frequencies (35–50 kHz) and similar transitions from between 70–90 kHz and 55–70 kHz (see Fig. 2e,f). There were also calls that lacked any abrupt changes in pitch. Often these calls were emitted in repeated temporal sequences (Holy & Guo 2005) and changed reproducibly with the succession of approach, mounting, and release behaviors that constitute the mating encounter. Before mounting, males usually called in either flat or continuous frequency-modulated USVs. However, when males mounted females, males shifted to frequency-modulated broken ‘step-like’ USVs with 70-kHz and 40/80 harmonic frequencies until the end of mounting (Wang et al. 2008).

image

Figure 2. Spectrograms of representative call types emitted by juvenile male C57BL/6J mice (P30) mice reunited in a home cage environment after 24 h of social isolation. Spectrograms include examples of an upward-modulated call (a), downward-modulated call (b), chevron (c), complex call (d) and punctuated call (e). The abrupt change in frequency in figure e is a pitch jump (p), indicated by the downward pointing arrow (f). Time (in seconds) is indicated by the X-axis, frequency in kHZ is indicated by the Y-axis, and relative intensity or loudness is indicated by color (see key).

Download figure to PowerPoint

Could these male vocalizations be relevant to affective prosody? Inferences that males derive a feeling of reward from social interactions with estrous females are warranted, based upon studies that use conditioned place preference (CPP) testing (and see below for discussion of CPP). Specifically, male mice prefer environments that have been associated with either mating (Kudwa et al. 2005, Popik et al. 2003) or even access to (Pankevich et al. 2006, Pierman et al. 2006) estrous female mice. The changing repertoire of male USVs through the mating process could reflect a shift from anticipation to consumption of sexual reward. In other words, these studies suggest that male mice may emit different peak frequencies that correlate with incentive salience vs. hedonic pleasure (see Berridge 2007).

Adult same-sex interactions

During male–male agonistic encounters, two types of calls can be expressed. V-shaped USVs encompass a broad frequency range and are emitted during naso-nasal contacts and body sniffing behaviors that precede fighting. A second set of calls consists of harmonics, or overtones, which are recorded during fighting behavior (Gourbal et al. 2004). These results are in agreement with the previous studies (Scott 1966) including observations that the number of audible vocalizations emitted during a male–male encounter correlates with time fighting and number of attacks (Brain et al. 1980, Morgret & Dengerink 1972). These audible vocalizations emitted during solicitation and mating, as there were similar to the ultrasonic vocalizations, are differences in USV structure that are associated with the anticipation vs. participation in social interactions. Taken together, the differences in frequency modulation associated with male anticipation and consumption of sexual vs. aggressive encounter indicate that these call patterns respond to differences in the affective nature of the social encounter.

There are fewer studies of vocalizations among female mice. Females express audible low-frequency vocalizations during copulation, particularly when they are not in estrous, consistent with the observation that they tend to avoid sexual encounters with males unless they are reproductively receptive. By contrast, female–female encounters engender USV production, especially when they were engaged in olfactory investigation of the other (Sewell 1970). Female mice emit a large number of USVs, typically emitted at 70 kHz, during the first minutes of social interaction (Gourbal et al. 2004, Moles et al. 2007). The rate of USV production among females appears to be responsive to levels of social motivation, experimentally imposed by food deprivation, estrous cycle, pregnancy and aging, such that USV rates positively correlate with levels of social investigation (Moles et al. 2007). Interestingly, just as estrous females produce fewer calls during same-sex interactions, brief exposure to a male also inhibits USV production (Maggio & Whitney 1985).

USVs of infant mice and the maternal response

Infant mice of postnatal day (PD) 1–4 are born blind and deaf (Fox 1965), have limited motor abilities, lack fur and subcutaneous fat and cool rapidly when displaced from the nest. When removed from the nest, they emit separation calls that elicit female retrieval. Under conditions of stress, cold and hunger, pups emit calls that engender maternal nest building, licking behaviors, and crouching behaviors that allow for access to teats (Noirot 1969). Rates of separation calls change with age and peak between PD 3 and PD 7, depending upon background strain (Branchi et al. 1998, Elwood & Keeling 1982, Hennessy et al. 1980, Scattoni et al. 2008b). By two weeks of age, juvenile mice no longer emit separation calls (Elwood & Keeling 1982, Noirot 1966).

As early as 1970, Sewell showed that lactating female wood mice (Apodemus sylvaticus) more frequently enter a compartment containing a loudspeaker emitting the recorded USVs vs. background noise or an artificial stimulus (Sewell 1970). Early studies also showed that lactating Mus musculus females preferentially approach ultrasounds within the frequency range of the natural calls (ranging from 40 to 80 kHz) vs. other ultrasonic sounds (Ehret & Haack 1981). More recently, a strain-dependent difference in the dynamic relationship between maternal responsiveness and pup calling rate was found. Using a three-compartment test structure, in which the mother could only reach her pups by crossing the central chamber which contained olfactory cues from a potentially infanticidal male, C57BL/6 mothers expressed higher maternal responsiveness vs. BALB/c females, and their pups emitted fewer calls than BALB/c pups (D’Amato et al. 2005). These data suggest that maternal responsiveness to pup calls, in turn, affects the rate that pups emit USVs.

Several studies show that USV production in response to separation and isolation can be a physiological response to a thermal challenge, e.g. a reflexive abdominal compression reaction in response to the cold that helps return venous blood to the heart (Blumberg & Alberts 1990, Blumberg & Sokoloff 2001). Additionally, pups vocalize when placed in a warm location (Branchi et al. 2004, Shair et al. 2003, Wöhr et al. 2008). In these cases, studies that employ knockout mice with alleles relevant to social bonding and separation distress suggest that separation calls are generated in response to affective changes. For instance, mice that lack a functional oxytocin allele, a molecule that plays a role in social bonding (Ferguson et al. 2000, 2002, Kavaliers et al. 2004, Mahler & Berridge 2009, Petrovic et al. 2008), emit fewer separation calls than their wild-type littermates (Winslow et al. 2000). Rates of separation calls are also influenced by the presence or absence of a mu-opioid receptor (Moles et al. 2004), which is a well-defined mediator of reward physiology and separation distress in rodents (Mahler & Berridge 2009, Panksepp et al. 1980).

Spectrographic analysis has showed that neonatal laboratory mice emit different kinds of USVs in response to varied environmental conditions to which the pup is exposed, such as odor from the nest, social isolation, low temperature, tactile stimulation or odor of an unfamiliar conspecific adult male (Branchi et al. 1998). For instance, isolated pups emit a high percentage of calls that contain abrupt breaks in frequency steps but an equal number of gradually modulated frequency calls relative to pups exposed to the odor of an unfamiliar, potentially infanticidal, adult male (Branchi et al. 1998). Variations in USV frequency modulation are also sensitive to the age of the pups, such that calls become stereotyped with maturation but remain acoustically distinct from adult USV patterns (Liu et al. 2003). See Fig. 1 for comparison of mouse vocalizations across development.

image

Figure 1. Spectrograms of call sequences differ among mice of varied ages and social contexts. Pup separation calls were collected from an 8-day-old mouse of the C57BL/6J strain approximately 1 min after removal from the nest and placement in a soundproof chamber at 23°C. Wriggling calls were recorded from pups within the litter of the C57BL/6J strain approximately 1 min after placing the microphone above the nest. Juvenile calls were recorded approximately 30 seconds after two male C57BL/6J mice (PD30) were reunited in a home cage environment after 24 h of social isolation. Calls emitted during female–female interactions were collected approximately 20 seconds after an intruder female was inserted into the cage of a resident female, both mice of the C57BL/6J strain after 3 days of social isolation. Calls emitted during male–female interactions were collected approximately 20 seconds after an adult female of the C57BL/6J strain was inserted into the cage of an adult male mouse of the C57BL/6J strain in his home cage environment. Calls emitted during male–male interactions were collected approximately 20 seconds after an intruder male of the C57BL/6J strain was inserted into the cage of a resident male mouse of the C57BL/6J strain in his home cage environment after 3 days of social isolation.

Download figure to PowerPoint

Mouse pups also produce ‘wriggling’ calls when struggling in the nest, mainly when pushing for the teats during suckling by the mother (Ehret 1975). These calls release at least three types of maternal behavior that include licking of pups, changes of suckling position, and nest building (Ehret & Bernecker 1986). Wriggling calls usually consist of a fundamental frequency near 4 kHz and overtones that can extend to a maximum frequency of about 20 kHz (Ehret & Bernecker 1986, Geissler & Ehret 2002, 2004). These calls elicit a specific neural activity. There is a differential response of C-fos immunoreactivity within the auditory cortex to synthetic wriggling calls played back to nursing females vs. similar synthetic wriggling USVs with a temporally displaced harmonic (Geissler & Ehret 2004). Interestingly, differences in immunoreactivity were more pronounced in the left hemisphere (Geissler & Ehret 2004), consistent with electrophysiological studies (Stiebler et al. 1997) and sharing similarities with human auditory processing (Ehret & Riecke 2002).

Genetics

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments

Call rates and frequency modulation of male USVs are responsive to genetic manipulations of endogenous reward pathways. For instance, targeted deletion of muscarinic receptor M5 results in an 80% decrease of male USVs production during sexual interaction. Male exposure to amphetamine, a direct ligand of D2 receptors, results in increased USV production, also responsive to targeted disruption of muscarinic receptors (Wang et al. 2008). Amphetamine can modulate dopamine release in the nucleus accumbens (Yeomans et al. 2000, 2001), thereby exerting a substantial role in appetitive behaviors (Berridge 2007, Ikemoto & Panksepp 1999, Kelley & Berridge 2002). Similarly, infant mice lacking functional mu-opioid receptors express reduced numbers of USVs during maternal separation (Moles et al. 2004), consistent with the evidence that enkephalin interactions with mu-opioid receptor can mediate social reward and isolation distress (Bertrand et al. 1997, Kalin et al. 1988, Panksepp et al. 1980, 1994, Vanderschuren et al. 1995).

Genetic manipulations that do not directly interact with incentive salience or hedonia can also modify call rate and call repertoire. For example, mice lacking functional components of circuits involved in social recognition, which include oxytocin and vasopressin receptor 1b, emit fewer calls (Scattoni et al. 2008a, Winslow & Insel 2002). Mice that lack functional alleles of genes associated with autistic-like social deficits, such as MECP2 and neuroligin 4 knockout mice, can express a diminished call rate (Jamain et al. 2008, Picker et al. 2006). Classification analysis has also showed that a spontaneous mutation (BTBR) and a targeted allelic replacement (foxp2 R552H) can influence the pup repertoire (Fujita et al. 2008, Scattoni et al. 2008b, Shu et al. 2005). This recent demonstration that ultrasound vocalizations can be modified by manipulations of foxp2, a gene involved in a familial form of speech impairment in humans and required for normal vocal development in songbirds, suggests that rodents may also be an important model for studying the neural and genetic basis of speech learning.

Mouse USVs and affect: theoretical considerations

Changes in subjective affective experience can be a proximal cause for changes in behavior. At a basic level, fear can induce freezing behavior, discomfort can induce withdrawal behavior, and anticipation of reward can induce an approach behavior. To the extent that specific aspects of the USV repertoire are associated with particular affective states, USV studies can provide insight to the genetic mechanisms that underlie affect regulation in normal psychological development and in mental illness.

Among humans, individuals make inferences to the quality of another person's experience based upon verbal communication or based upon observations of an individual's behavior. One means of communicating personal experience is through use of words. Self-report is an essential analytical tool for human research and clinical diagnosis, the basis of tremendous advances in psychological and psychiatric medicine. However, self-report has scientific and philosophical limitations. Bertrand Russell (1912) identified the problem: while words or labels are used to describe universal subjective states, it remains unknown whether these labels identify identical internal experiences. For example, two individuals can use the label ‘red’ to describe an apple but the red apple may appear as red-orange to one person and red-purple to another. It is inherently unknown whether both individuals have identical internal experiences, because of perceptual variations, such as differences in vision or brain function. Differences in sex, age, cultural context and mental illness further contribute to variation in how words label subjective experiences. For instance, post-traumatic stress disorder might impose an atypical sensitivity to stimuli that may be inadequately described with the existing verbal repertoire. Discrete labels used to communicate individual perceptions, no matter how basic or complicated, have limitations in terms of describing internal experience.

To gain greater insight to the affective experience of individuals, new assessment tools have been developed that do not depend upon verbal report. Directionality of eye-gaze (Klin et al. 2002, Wolf et al. 2008) and patterns of brain activity provide insights to how autistic individuals attend to social interactions (Baron-Cohen et al. 1999). Assessments of heart rate variability provide insight to how children experience distress of others (Eisenberg et al. 1988). To gain insight to the etiology of developmental disorders, there are ongoing efforts to identify the psychological experiences that are experiences during mental illness. For example, there is ongoing controversy about whether some forms of autism can result from social anxiety (Kuusikko et al. 2008), deficits in temporal cognition (Boucher et al. 2007) or central coherence (Briskman et al. 2001, Happe et al. 2001). Just as efforts to infer psychological experience can be useful for elucidating mechanisms underlying mental illness, the same issues are important for mouse research. If a knockout mouse expresses low levels of social approach, how do we know whether the targeted allele models autism, vs. depression, vs. shyness?

Such questions are rather new to behavioral neuroscience. Considerable precedence in the history of philosophy, extending back to the work of Rene Descartes (1637), maintains that animals are ‘automata’ or machine-like, in contrast to ‘sentient’ or soulful humans. With the advent of cognitive and affective neuroscience, these Cartesian distinctions are no longer relevant, but it is important to be careful about inferences to rodent affective experience (Panksepp 1998, Schneirla 1959). Such inferences require consideration of the theoretical framework of affective neuroscience, including operant, fear and preference conditioning paradigms, as well as studies of functional anatomy and brain/systems physiology (Panksepp 1998). Such an approach provides working hypotheses for comparative studies of affective prosody that can be subject to falsification.

Operant and place preference conditioning are used to establish anticipation and consumption of rewards (Bardo & Bevins 2000, Kelley et al. 2002, Moles et al. 2004), and aversive conditions can be identified by conditioned fear learning paradigms (Falls et al. 1997, LeDoux et al. 1988, Paylor et al. 1994). Emotional responses to stimuli can also be inferred from studies of functional anatomy, particularly the highly conserved limbic structures in the brain (MacLean 1990) and the underlying physiological systems that mediate affect regulation, including dopamine, serotonin, corticosterone and endogenous opiates (Panksepp 1998). Drugs of abuse, such as opiates and amphetamine, are also useful, because they can influence natural reward systems (Abarca et al. 2002, Bardo & Bevins 2000, Kelley & Berridge 2002, Reith & Selmeci 1992, van Ree et al. 1999). Pharmaceuticals that modulate affective states in humans can be employed that influence analogous behaviors in mouse models (Holsboer 2001, Hunsberger et al. 2007, Kato 2006, Pezet & Malcangio 2004, Rupniak et al. 2001).

In summary, assessments of prosody in mice along with measures of neural and behavioral correlates of motivated behavior, allow for greater reliability in inferences to subjective experience. Such assessments are important for translational applications of mouse research to mental illness. While human vocal patterns are vastly more complex with regard to frequency modulation, timing, overtones, and range of sound produced, and may provide more nuanced emotional content, and studies of human language can assess the temporal associations between prosodic content and referential aspects of language, basic elements of prosodic content in mice are measurable and have been associated with rewarding and aversive conditions. Thus, studies of prosody in humans and mice may yield apples-to-apples comparisons useful for subjective inference.

Mouse USVs and affect: practical considerations

Behavioral associations with USV production

Juvenile mice emit USVs when meeting a littermate after 24 h of social isolation. When USVs of juvenile C57BL/6J (B6) and BALBc/J (BALB) mice are compared during reunion, there are clear differences in the kinds of calls that they emit. For example, there are more downward-modulated calls among reunited B6 juveniles and more upward-modulated and chevron calls among BALB juveniles (see Fig. 2 for example spectrograms).

Differences in USV production between genetic variants of mice could be explained as products of discrete genetic contributions to the anatomies of the larynx or labia. Alternatively, there may be particular calls that are associated with state, such as the motivation to solicit social interaction. To assess the likelihood of these opposing hypotheses, we compared the usage of various call types by different individuals within a strain that express differences in social approach behaviors. Individual B6 and BALB juveniles express more USVs when they are engaged in more vigorous social approach behaviors (Panksepp et al. 2007). During more vigorous social approach behaviors, B6 mice disproportionally express calls that are of a higher pitch and more downward-modulated. These differences in B6 vocal repertoire suggest the possibility that different call types correspond to different degrees of social motivation or function to engender discrete levels of motivation in others. Also important, selective B6 use of particular call types during higher levels of social interaction was specific to B6 mice. BALB mice that engaged in vigorous social interactions expressed all call types at a higher rate. This finding indicates that the degree of repertoire flexibility within a strain is also dependent upon genetic background.

Rodents prefer social encounter to isolation, consistent with classical theories of motivated behavior (Bardo & Bevins 2000, Berridge & Robinson 2003, Tzschentke 1998) that underscore a role for reward and punishment in behavioral approach and withdrawal (Glickman & Schiff 1967, Schneirla 1959, Young 1959). Mouse responses to conditioned place preference (CPP) tests show that they can find social encounters rewarding and social isolation aversive. In a standard CPP experiment, mice are placed in one of two distinct environments. For instance, the beddings of the two environments may be different (one is aspen and the other is paper), the walls may have horizontal vs. vertical lines, or the floors may have circular holes in them or exist as a parallel grid. During the conditioning phases of these experiments, the test mouse is housed successively in either one or the other environment. The mouse has access to a putative reward (e.g. peanut butter, chocolate, cocaine, morphine) in one environment but not in the alternate environment. If the mouse finds the test stimulus rewarding, then through repeated association, the environment associated with access to the reward eventually elicits approach behavior. At the end of the conditioning phase, the mouse is placed in a testing structure that does not contain the reward but contains both of the ‘conditioned’ environments. The dependent measure of CPP is the difference in the amount of time spent in the environment associated with the presence of the putative reward vs. the environment paired with its absence. If the stimulus is rewarding, the mouse should spend more time in the environment that is paired with it. Among rodents, CPP tests have showed reward processes during different kinds of social encounters, including play (Calcagnetti & Schechter 1992, Douglas et al. 2004), sexual interactions (Camacho et al. 2004, Jenkins & Becker 2003), mother–infant bonding (Mattson et al. 2001, Weller et al. 2001) and even aggression (Martinez et al. 1995).

CPP experiments can also be helpful in determining whether mouse strains that express different USV repertoires experience different levels of social motivation. For instance, B6 mice show a strong place preference for bedding environments that have been associated with access to age-matched juveniles vs. beddings that are paired with social isolation (Panksepp & Lahvis 2007). These results suggest the possibility that the vocal repertoire of B6 mice may be associated with the degree of social reward; that there is a relationship between call pattern and various levels of social motivation. We can also gain insight to useful approaches for studying mouse USVs from insightful experiments of rat vocalizations. Rats emit high-frequency (50 kHz) calls when they anticipate a future reward or when they are experiencing the reward, and emit lower frequency (22 kHz) USVs under aversive conditions (Burgdorf et al. 2008, Knutson et al. 1999, Schwarting et al. 2007, Wöhr & Schwarting 2009). In addition to conditioning experiments, studies with operant tasks indicate that rats will self-administer playbacks of recordings of 50 kHZ ‘trill’ calls but not 22 kHz calls (Burgdorf et al. 2008). Similar kinds of evaluations might be useful for interpreting particular mouse USVs. It would be very useful to know whether specific call types associate with different CPP responses to specific drugs. Measures of mouse USVs have the potential to provide insight to real-time fluctuations in affect that we cannot obtain through CPP or fear conditioning testing. Experiments that take advantage of the differences in social motivation that accompany variations in the duration of social isolation or the time of day when social encounter occurs (Panksepp et al. 2008) could be used to discern how call patterns and responses to them change with social conditions.

Behavioral and systemic responses to vocalizations

Studies of animal acoustic communication utilize behavioral responses to recordings or ‘playbacks’ of particular kinds of animal calls to ascertain the meaning of various signals. In a series of experiments, we found that mice can become differentially fearful of a tone that is temporally associated with the vocalizations of a distressed mouse. This experiment involves a cue-conditioned fear learning paradigm (LeDoux et al. 1988). A standard fear conditioning procedure entails presenting an animal with a neutral stimulus, such as a tone (conditioned stimulus, CS), forward paired with an aversive stimulus, such as an electrical shock (unconditioned stimulus, UCS). Upon repeated administration of the paired CS–UCS, mice acquire a robust freezing behavior in response to presentation of the CS only. When B6 and BALB mice observe others undergo this fear conditioning procedure, only B6 mice are capable of learning from the distress of others. B6 also acquire the freezing response to the tone if they simply hear playbacks of the vocalizations of other distressed mice (played back 2-second recordings of the vocalizations of shocked mice) in association with the 30-second tone. Control experiments indicate that the BALB mice can hear the calls, because they respond to an environmental cue (the tone) of an overlapping frequency and energy level (approximately 85 dB). Importantly, heart rate deceleration is expressed in B6 when demonstrator mice undergo fear conditioning, but BALB mice do not show heart rate deceleration. Depression of heart rate can be associated with the empathic response to other's distress and this occurs among children more capable of detecting distress among others (Eisenberg et al. 2006). These studies indicate that fear can be perceived through vocal signals under the appropriate genetic background.

Brain activity in response to vocalizations

To assess the salience of different call types, researchers are beginning to examine freezing behavior, heart rate changes or other behavioral end-points in response to playbacks of auditory cues, such as distress vocalizations (Jeon et al. 2010, Knapska et al. 2006, Liu et al. 2006, Sadananda et al. 2008). For instance, variations in USV frequency modulation are sensitive to the age of the pups, with distinct influences on activity of the auditory cortex (Liu et al. 2003). In fact, experience appears to change neural processing of auditory stimuli; maternal auditory processing of pup USVs is distinct from that of naïve females (Liu et al. 2006, Liu & Schreiner 2007).

Future directions

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments

USV analysis

There are a variety of approaches to vocal analysis, ranging from classification schemes to principal components analysis to hidden-Markov approaches. Various software programs have been developed to serve different purposes and each has its own benefits. Software programs can be employed to directly measure USV s, such as Avisoft SASLabPro (Panksepp et al. 2007, Scattoni et al. 2008a, Wöhr et al. 2008), others are designed to dissociate calls based upon highly nuanced spectral features, such as continuity and entropy (Tchernichovski et al. 2001), or identify calls in low signal-to-noise conditions (Mellinger 2009). Investigators also utilize custom MATLAB software programs to analyze frequency modulation in mouse USVs (Liu et al. 2006). Pattern recognition in USV sequence is also aided by the application of advanced statistical approaches (Ren et al. 2009). In this regard, future studies will likely utilize a variety of software approaches to obtain different kinds of information from calls, ranging from simple classifications of relatively similar call types (Panksepp et al. 2007) to discriminations of quite subtle changes in frequency modulation within a single call type. Differences in affective content might then be discerned by use of playbacks in combination with measures of brain activity, heart rate changes, behavioral responses, or other parameters that allow us to make inferences to affective response.

Complex environments

The rodent has long been considered a mammalian substitute for the human patient (Beach 1950), but when concentrating on a single, increasingly exploited, lab species, it has to be taken in mind that such a species is the ‘ultimate’ product (a variable genetic pool fragmented in a variety of local populations) of species-specific phylogenetic and epigenetic processes. Laboratory mice have been strongly selected for husbandry in a small cage, where there are limited opportunities for temporal and geographic variations in food access, social encounter, temperature, diurnal rhythms, encounter with predators, or exploration. By contrast, feral mice, by definition strictly associated to human settlements (Bronson 1979), show highly variable adaptive strategies that are not promoted by standard cage housing. It is likely that laboratory mice are thus not raised to vocalize in response to the more complex variety of social-emotional states that accompany a multifaceted environment. In this regard, wild-derived mice provide potentially useful opportunities to dissociate USV patterns (Musolfa et al. 2010, Kalcounis-Rueppell et al. 2010). A truly, genuine, comparative approach should be based on a much broader range of mouse experiences and representative species: the search for functional and/or structural invariance could be a fruitful ‘zoo-semeiotic’ perspective (sensu Sebeok) (Sebeok 1972). Studies with feral mice, as well as other feral rodent species, might provide a high degree of fidelity between call type and affective state.

More substantive vocal behaviors might also be showed by naturalistic or semi-naturalistic settings (Alleva et al. 1994, Portfors 2007). While mouse vocalizations are sensitive to targeted loss-of-function mutations in genes involved in affect regulation, language development, social bonding and autism, we may gain greater insight to how these mutations modify call patterns by expanding mouse developmental histories. Genetic variants can be raised in complex settings to expand their emotional experience and vocal repertoire. Rearing could entail geographic and temporal variation, such as random temporal access to food rewards, such as peanut butter, and stressors, such as cat urine, within a complex three-dimensional environment. Mice raised in environments that incorporate rewarding and aversive stimuli, in the context of more complex social paradigms, might provide a useful model for delineating relationships between affective states and specific call types.

Summary

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments
  • Assessments of frequency modulation provide researchers with an ability to study USVs in a fashion that has translational relevance to prosodic deficits in mental illness. Measures of mouse USVs have the potential to provide a window to real-time changes in affective state that are not accessible by CPP or fear conditioning tests.
  • Inferences about call meaning should be considered within the context of ethologically relevant behaviors or traditional assessments of reward and aversion (e.g. conditioning experiments) and through the use of heart rate monitoring, assessments of brain activity, and other physiological indicators of affective response.
  • Mutant genetic models that are relevant to reward neurobiology, language, autism and social bonding can express abnormal USV patterns. Use of multiple statistical approaches for bioacoustic analysis, including clustering and hidden-Markov approaches, can help elucidate associations between USV structure and function.
  • By using wild-derived mice as rearing mice in more complex environments, researchers might also gain greater insight to the discrete functions, individual calls or call sequences within the diversity of the vocal repertoire.

References

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments
  • Abarca, C., Albrecht, U. & Spanagel, R. (2002) Cocaine sensitization and reward are under the influence of circadian genes and rhythm. Proc Natl Acad Sci U S A 99, 90269030.
  • Abdi, Z. & Sharma, T. (2004) Social cognition and its neural correlates in schizophrenia and autism. CNS Spectrums 9, 335343.
  • Alleva, E., Fasolo, A., Lipp, H.P., Nadel, L. & Ricceri, L. (1994) Behavioural Brain Research in Naturalistic and Semi-naturalistic Settings. Kluwer Academic Publishers, Dordrecht, The Netherlands.
  • Alpert, M., Rosenberg, S.D., Pouget, E.R. & Shaw, R.J. (2000) Prosody and lexical accuracy in flat affect schizophrenia. Psychiatry Res 97, 107118.
  • Amorosa, H. (1992) Disorders of vocal signaling in children. In Papousek, U., Jurgens, U. & Papousek, M. (eds), Nonverbal Vocal Communication: Comparative and Developmental Approaches. Cambridge University Press, Cambridge, UK, pp. 192204.
  • Bach, D.R., Buxtorf, K., Grandjean, D. & Strik, W.K. (2009) The influence of emotion clarity on emotional prosody identification in paranoid schizophrenia. Psychol Med 39, 927938.
  • Baltaxe, C.A. (1984) Use of contrastive stress in normal, aphasic, and autistic children. J Speech Hear Res 27, 97105.
  • Baltaxe, C.A. & Guthrie, D. (1987) The use of primary sentence stress by normal, aphasic, and autistic children. J Autism Dev Disord 17, 255271.
  • Bardo, M.T. & Bevins, R.A. (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology 153, 3143.
  • Baron-Cohen, S., Ring, H.A., Wheelwright, S., Bullmore, E.T., Brammer, M.J., Simmons, A. & Williams, S.C. (1999) Social intelligence in the normal and autistic brain: an fMRI study. Eur J Neurosci 11, 18911898.
  • Beach, F.A. (1950) The snark was a boojum. Am Psychol 5, 115124.
  • Beatty, W.W., Orbelo, D.M., Sorocco, K.H. & Ross, E.D. (2003) Comprehension of affective prosody in multiple sclerosis. Mult Scler 9, 148153.
  • Benke, T., Bosch, S. & Andree, B. (1998) A study of emotional processing in Parkinson's disease. Brain Cogn 38, 3652.
  • Berridge, K.C. (2007) The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology 191, 391431.
  • Berridge, K.C. & Robinson, T.E. (2003) Parsing reward. Trends Neurosci 26, 507513.
  • Bertrand, E., Smadja, C., Mauborgne, A., Roques, B.P. & Dauge, V. (1997) Social interaction increases the extracellular levels of [Met]enkephalin in the nucleus accumbens of control but not of chronic mild stressed rats. Neuroscience 80, 1720.
  • Blumberg, M.S. & Alberts, J.R. (1990) Ultrasonic vocalizations by rat pups in the cold: an acoustic by-product of laryngeal braking? Behav Neurosci 104, 808817.
  • Blumberg, M.S. & Sokoloff, G. (2001) Do infant rats cry? Psychol Rev 108, 8395.
  • Boucher, J., Pons, F., Lind, S. & Williams, D. (2007) Temporal cognition in children with autistic spectrum disorders: tests of diachronic thinking. J Autism Dev Disord 37, 14131429.
  • Bozikas, V.P., Kosmidis, M.H., Anezoulaki, D., Giannakou, M., Andreou, C. & Karavatos, A. (2006) Impaired perception of affective prosody in schizophrenia. J Neuropsychiatry Clin Neurosci 18, 8185.
  • Brain, P.F., Benton, D., Cole, C. & Prowse, B. (1980) A device for recording submissive vocalizations of laboratory mice. Physiol Behav 24, 10031006.
  • Branchi, I., Santucci, D., Vitale, A. & Alleva, E. (1998) Ultrasonic vocalizations by infant laboratory mice: a preliminary spectrographic characterization under different conditions. Dev Psychobiol 33, 249256.
  • Branchi, I., Santucci, D., Puopolo, M. & Alleva, E. (2004) Neonatal behaviors associated with ultrasonic vocalizations in mice (Mus musculus): a slow-motion analysis. Dev Psychobiol 44, 3744.
  • Briskman, J., Happe, F. & Frith, U. (2001) Exploring the cognitive phenotype of autism: Weak “central coherence” in parents and siblings of children in autism: II. Real-life skills and preferences. J Child Psychol Psychiatry 42, 309316.
  • Bronson, F.H. (1979) The reproductive ecology of the house mouse. Q Rev Biol 54, 265299.
  • Burgdorf, J., Kroes, R.A., Moskal, J.R., Pfaus, J.G., Brudzynski, S.M. & Panksepp, J. (2008) Ultrasonic vocalizations of rats (Rattus norvegicus) during mating, play, and aggression: behavioral concomitants, relationship to reward, and self-administration of playback. J Comp Psychol 122, 357367.
  • Calcagnetti, D.J. & Schechter, M.D. (1992) Place conditioning reveals the rewarding aspect of social interaction in juvenile rats. Physiol Behav 51, 667672.
  • Camacho, F., Sandoval, C. & Paredes, R.G. (2004) Sexual experience and conditioned place preference in male rats. Pharmacol Biochem Behav 78, 419425.
  • Cohen, A.S. & Docherty, N.M. (2005) Effects of positive affect on speech disorder in schizophrenia. J Nerv Ment Dis 193, 839842.
  • Jeon, D., Kim, S., Chetana, M., Jo, D., Ruley, H.E., Lin, S.-Y., Rabah, D., Kinet, J.-P. & Shin, H.-S. (2010) Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC. Nat Neurosci 13, 482488.
  • D’Amato, F.R., Scalera, E., Sarli, C. & Moles, A. (2005) Pups call, mothers rush: does maternal responsiveness affect the amount of ultrasonic vocalizations in mouse pups? Behav Genet 35, 103112.
  • Decartes, R. (2009) Discourse on the Method. Oxford University Press, Oxford.
  • Derntl, B., Finkelmeyer, A., Toygar, T.K., Hulsmann, A., Schneider, F., Falkenberg, D.I. & Habel, U. (2009) Generalized deficit in all core components of empathy in schizophrenia. Schizophr Res 108, 197206.
  • Diehl, J.J., Bennetto, L., Watson, D., Gunlogson, C. & Mc-Donough, J. (2008) Resolving ambiguity: a psycholinguistic approach to understanding prosody processing in high-functioning autism. Brain Lang 106, 144152.
  • Douglas, L.A., Varlinskaya, E.I. & Spear, L.P. (2004) Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners. Dev Psychobiol 45, 153162.
  • Ehret, G. (1975) Schallsignale der Hausmaus (Mus Musculus). Behaviour 52, 3856.
  • Ehret, G. & Bernecker, C. (1986) Low-frequency sound communication by mouse pups (Mus musculus): wriggling calls release maternal behaviour. Anim Behav 34, 821830.
  • Ehret, G. & Haack, B. (1981) Categorical perception of mouse pup ultrasound by lactating females. Naturwissenschaften 68, 208209.
  • Ehret, G. & Riecke, S. (2002) Mice and humans perceive multiharmonic communication sounds in the same way. Proc Natl Acad Sci U S A 99, 479482.
  • Eisenberg, N., Fabes, R.A., Bustamante, D., Mathy, R.M., Miller, P.A. & Lindholm, E. (1988) Differentiation of vicariously induced emotional reactions in children. Dev Psychol 24, 237246.
  • Eisenberg, N., Fabes, R.A. & Spinard, T.L. (2006) Prosocial development. In Eisenberg, N. (ed), Handbook of Child Psychology. John Wiley & Sons Inc., New Jersey, pp. 646718.
  • Elwood, R.W. & Keeling, F. (1982) Temporal organization of ultrasonic vocalizations in infant mice. Dev Psychobiol 15, 221227.
  • Emerson, C.S., Harrison, D.W. & Everhart, D.E. (1999) Investigation of receptive affective prosodic ability in school-aged boys with and without depression. Neuropsychiatry Neuropsychol Behav Neurol 12, 102109.
  • Falls, W.A., Carlson, S., Turner, J.G. & Willott, J.F. (1997) Fear-potentiated startle in two strains of inbred mice. Behav Neurosci 111, 855861.
  • Ferguson, J.N., Young, L.J., Hearn, E.F., Matzuk, M.M., Insel, T.R. & Winslow, J.T. (2000) Social amnesia in mice lacking the oxytocin gene. Nat Genet 25, 284288.
  • Ferguson, J.N., Young, L.J. & Insel, T.R. (2002) The neuroendocrine basis of social recognition. Front Neuroendocrinol 23, 200224.
  • Fernald, A. (1989) Intonation and communicative intent in mothers' speech to infants: is the melody the message? Child Dev 60, 14971510.
  • Fine, J., Bartolucci, G., Ginsberg, G. & Szatmari, P. (1991) The use of intonation to communicate in pervasive developmental disorders. J Child Psychol Psychiatry 32, 771782.
  • Fox, M. (1965) Reflex-ontogeny and behavioural development of the mouse. Anim Behav 13, 234241.
  • Freeman, T.W., Hart, J., Kimbrell, T. & Ross, E.D. (2009) Comprehension of affective prosody in veterans with chronic posttraumatic stress disorder. The Journal of Neuropsychiatry and Clinical Neurosciences 21, 5258.
  • Fujita, E., Tanabe, Y., Shiota, A., Ueda, M., Suwa, K., Momoi, M.Y. & Momoi, T. (2008) Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells. Proceedings of the National Academy of Sciences of the United States of America 105, 31173122.
  • Fujiwara, H., Shimizu, M., Hirao, K., Miyata, J., Namiki, C., Sawamoto, N., Fukuyama, H., Hayashi, T. & Murai, T. (2008) Female specific anterior cingulate abnormality and its association with empathic disability in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32, 17281734.
  • Geissler, D.B. & Ehret, G. (2002) Time-critical integration of formants for perception of communication calls in mice. Proc Natl Acad Sci U S A 99, 90219025.
  • Geissler, D.B. & Ehret, G. (2004) Auditory perception vs. recognition: representation of complex communication sounds in the mouse auditory cortical fields. Eur J Neurosci 19, 10271040.
  • Glickman, S.E. & Schiff, B.B. (1967) A biological theory of reinforcement. Psychol Rev 74, 81109.
  • Golan, O., Baron-Cohen, S., Hill, J.J. & Rutherford, M.D. (2007) The ‘Reading the Mind in the Voice’ test-revised: a study of complex emotion recognition in adults with and without autism spectrum conditions. J Autism Dev Disord 37, 10961106.
  • Gourbal, B.E., Barthelemy, M., Petit, G. & Gabrion, C. (2004) Spectrographic analysis of the ultrasonic vocalisations of adult male and female BALB/c mice. Naturwissenschaften 91, 381385.
  • Hagerman, R.J., Jackson, A.W., Levitas, A., Rimland, B. & Braden, M. (1986) An analysis of autism in fifty males with the fragile X syndrome. American Journal of Medical Genetics 23, 359374.
  • Haker, H. & Rossler, W. (2009) Empathy in schizophrenia: impaired resonance. Eur Arch Psychiatry Clin Neurosci 259, 352361.
  • Happe, F., Briskman, J. & Frith, U. (2001) Exploring the cognitive phenotype of autism: weak “central coherence” in parents and siblings of children with autism: I. Experimental tests. J Child Psychol Psychiatry 42, 299307.
  • Hennessy, M.B., Li, J., Lowe, E.L. & Levine, S. (1980) Maternal behavior, pup vocalizations, and pup temperature changes following handling in mice of 2 inbred strains. Dev Psychobiol 13, 573584.
  • Holsboer, F. (2001) Prospects for antidepressant drug discovery. Biol Psychol 57, 4765.
  • Holy, T.E. & Guo, Z. (2005) Ultrasonic songs of male mice. PLoS Biol 3, e386.
  • Houseknecht, C.R. (1968) Sonographic analysis of vocalizations of three species of mice. J Mammal 49, 555560.
  • Hunsberger, J.G., Newton, S.S., Bennett, A.H., Duman, C.H., Russell, D.S., Salton, S.R. & Duman, R.S. (2007) Antidepressant actions of the exercise-regulated gene VGF. Nat Med 13, 14761482.
  • Ikemoto, S. & Panksepp, J. (1999) The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Rev 31, 641.
  • Jamain, S., Radyushkin, K., Hammerschmidt, K., Granon, S., Boretius, S., Varoqueaux, F., Ramanantsoa, N., Gallego, J., Ronnenberg, A., Winter, D., Frahm, J., Fischer, J., Bourgeron, T., Ehrenreich, H. & Brose, N. (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci U S A 105, 17101715.
  • Jenkins, W.J. & Becker, J.B. (2003) Female rats develop conditioned place preferences for sex at their preferred interval. Horm Behav 43, 503507.
  • Kalcounis-Rueppell, M.C., Petric, R., Briggs, J.R., Carney, C., Marshall, M.M., Willse, J.T., Rueppell, O., Ribble, D.O. & Crossland, J.P. (2010) Differences in ultrasonic vocalizations between wild and laboratory California mice (Peromyscus californicus). PLoS One 5: DOI: 10.1371/journal.pone.0009705, 110.
  • Kalin, N.H., Shelton, S.E. & Barksdale, C.M. (1988) Opiate modulation of separation-induced distress in non-human primates. Brain Res 440, 285292.
  • Kato, T. (2006) The role of mitochondrial dysfunction in bipolar disorder. Drug News Perspect 19, 597602.
  • Kavaliers, M., Choleris, E., Agmo, A. & Pfaff, D.W. (2004) Olfactory-mediated parasite recognition and avoidance: linking genes to behavior. Horm Behav 46, 272283.
  • Kelley, A.E. & Berridge, K.C. (2002) The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 22, 33063311.
  • Kelley, A.E., Bakshi, V.P., Haber, S.N., Steininger, T.L., Will, M.J. & Zhang, M. (2002) Opioid modulation of taste hedonics within the ventral striatum. Physiol Behav 76, 365377.
  • Klin, A., Jones, W., Schultz, R., Volkmar, F. & Cohen, D. (2002) Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism. Arch Gen Psychiatry 59, 809816.
  • Knapska, E., Nikolaev, E., Boguszewski, P., Walasek, G., Blaszczyk, J., Kaczmarek, L. & Werka, T. (2006) Between-subject transfer of emotional information evokes specific pattern of amygdala activation. Proc Natl Acad Sci U S A 103, 38583862.
  • Knutson, B., Burgdorf, J. & Panksepp, J. (1999) High-frequency ultrasonic vocalizations index conditioned pharmacological reward in rats. Physiol Behav 66, 639643.
  • Kudwa, A., Dominguez-Salazar, E., Cabrera, D., Sibley, D. & Rissman, E. (2005) Dopamine D5 receptor modulates male and female sexual behavior in mice. Psychopharmacology 180, 206214.
  • Kuhl, P.K., Coffey-Corina, S., Padden, D. & Dawson, G. (2005) Links between social and linguistic processing of speech in preschool children with autism: behavioral and electrophysiological measures. Dev Sci 8, F1F12.
  • Kuusikko, S., Pollock-Wurman, R., Jussila, K., Carter, A.S., Mattila, M.-L., Ebeling, H., Pauls, D.L. & Moilanen, I. (2008) Social anxiety in high-functioning children and adolescents with autism and Asperger syndrome. J Autism Dev Disord 38, 16971709.
  • LeDoux, J.E., Iwata, J., Cicchetti, P. & Reis, D.J. (1988) Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci 8, 25172529.
  • Leentjens, A.F., Wielaert, S.M., van Harskamp, F. & Wilmink, F.W. (1998) Disturbances of affective prosody in patients with schizophrenia; a cross sectional study. J Neurol Neurosurg Psychiatry 64, 375378.
  • Leitman, D.I., Ziwich, R., Pasternak, R. & Javitt, D.C. (2006) Theory of Mind (ToM) and counterfactuality deficits in schizophrenia: misperception or misinterpretation? Psychol Med 36, 10751083.
  • Liu, R.C. & Schreiner, C.E. (2007) Auditory cortical detection and discrimination correlates with communicative significance. PLoS Biol 5, e173.
  • Liu, R.C., Miller, K.D., Merzenich, M.M. & Schreiner, C.E. (2003) Acoustic variability and distinguishability among mouse ultrasound vocalizations. J Acoust Soc Am 114, 34123422.
  • Liu, R.C., Linden, J.F. & Schreiner, C.E. (2006) Improved cortical entrainment to infant communication calls in mothers compared with virgin mice. Eur J Neurosci 23, 30873097.
  • Lord, C., Risi, S., Lambrecht, L., Cook, E.H.Jr., Leventhal, B.L., DiLavore, P.C., Pickles, A. & Rutter, M. (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism & Developmental Disorders 30, 205223.
  • MacLean, P.D. (1990) The Triune Brain in Evolution: Role in Paleocerebral Functions. Plenum Press, New York.
  • Maggio, J.C. & Whitney, G. (1985) Ultrasonic vocalizing by adult female mice (Mus musculus). J Comp Psychol 99, 420436.
  • Maggio, J.C., Maggio, J.H. & Whitney, G. (1983) Experience-based vocalization of male mice to female chemosignals. Physiol Behav 31, 269272.
  • Mahler, S.V. & Berridge, K.C. (2009) Which cue to “want?” Central amygdala opioid activation enhances and focuses incentive salience on a prepotent reward cue. J Neurosci 29, 65006513.
  • Martinez, M., Guillen-Salazar, F., Salvador, A. & Simon, V.M. (1995) Successful intermale aggression and conditioned place preference in mice. Physiol Behav 58, 323328.
  • Mattson, B.J., Williams, S., Rosenblatt, J.S. & Morrell, J.I. (2001) Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav Neurosci 115, 683694.
  • McCann, J., Peppe, S., Gibbon, F.E., O’Hare, A. & Rutherford, M. (2007) Prosody and its relationship to language in school-aged children with high-functioning autism. Int J Lang Commun Disord 42, 682702.
  • Mellinger, D.K. (2009) Noise-resistant acoustic measurements implemented in user-friendly software. J Acoust Soc Am 125, 2737.
  • Moles, A., Kieffer, B.L. & D’Amato, F.R. (2004) Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science 304, 19831986.
  • Moles, A., Costantini, F., Garbugino, L., Zanettini, C. & D’Amato, F.R. (2007) Ultrasonic vocalizations emitted during dyadic interactions in female mice: a possible index of sociability? Behav Brain Res 182, 223230.
  • Monnot, M., Nixon, S., Lovallo, W. & Ross, E. (2001) Altered emotional perception in alcoholics: deficits in affective prosody comprehension. Alcohol Clin Exp Res 25, 362369.
  • Monnot, M., Lovallo, W.R., Nixon, S.J. & Ross, E. (2002) Neurological basis of deficits in affective prosody comprehension among alcoholics and fetal alcohol-exposed adults. J Neuropsychiatry Clin Neurosci 14, 321328.
  • Morgret, M.K. & Dengerink, H.A. (1972) The squeal as an indicator of aggression in mice. Behav Res Methods Instrumentation 4, 138140.
  • Murphy, D. & Cutting, J. (1990) Prosodic comprehension and expression in schizophrenia. J Neurol Neurosurg Psychiatry 53, 727730.
  • Musolfa, K., Hoffmanna, F. & Penna, D.J. (2010) Ultrasonic courtship vocalizations in wild house mice, Mus musculus musculus. Anim Behav 79, 757764.
  • Noirot, E. (1966) Ultra-sounds in young rodents. I. Changes with age in albino mice. Anim Behav 14, 459462.
  • Noirot, E. (1969) Changes in responsiveness to young in the adult mouse. V. Priming. Anim Behav 17, 542546.
  • Nyby, J. (1983) Ultrasonic vocalizations during sex behavior of male house mice (Mus musculus): a description. Behav Neural Biol 39, 128134.
  • Nyby, J.G. (2001) Auditory communication among adults. In Willott, J.F. (ed), Handbook of Mouse Auditory Research: From Behavior to Molecular Biology. CRC Press, Boca Raton, Florida, pp. 318.
  • Nyby, J. & Whitney, G. (1978) Ultrasonic communication of adult myomorph rodents. Neurosci Biobehav Rev 2, 114.
  • O’Keeffe, F., Murray, B., Coen, R., Dockree, P., Bellgrove, M., Garavan, H., Lynch, T. & Robertson, I. (2007) Loss of insight in frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy. Brain: A Journal of Neurology 130, 753764.
  • Orbelo, D.M., Grim, M.A., Talbott, R.E. & Ross, E.D. (2005) Impaired comprehension of affective prosody in elderly subjects is not predicted by age-related hearing loss or age-related cognitive decline. Journal of Geriatric Psychiatry & Neurology 18, 2532.
  • Pankevich, D.E., Cherry, J.A. & Baum, M.J. (2006) Accessory olfactory neural Fos responses to a conditioned environment are blocked in male mice by vomeronasal organ removal. Physiol Behav 87, 781788.
  • Panksepp, J. (1998) Affective Neuroscience: The Foundations of Human and Animal Emotions. Oxford University Press, Oxford.
  • Panksepp, J.B. & Lahvis, G.P. (2007) Social reward among juvenile mice. Genes Brain Behav 6, 661671.
  • Panksepp, J., Herman, B.H., Vilberg, T., Bishop, P. & DeEskinazi, F.G. (1980) Endogenous opioids and social behavior. Neurosci Biobehav Rev 4, 473487.
  • Panksepp, J., Nelson, E. & Siviy, S. (1994) Brain opioids and mother-infant social motivation. Acta Paediatr Suppl 397, 4046.
  • Panksepp, J.B., Jochman, K., Kim, J.U., Koy, J.J., Wilson, E.D., Chen, Q., Wilson, C.R. & Lahvis, G.P. (2007) Affiliative behavior, ultrasonic communication and social reward are influenced by genetic variation in adolescent mice. PLoS ONE 2: DOI: 10.1371/journal.pone.0000351, 113.
  • Panksepp, J.B., Wong, J.C., Kennedy, B.C. & Lahvis, G.P. (2008) Differential entrainment of a social rhythm in adolescent mice. Behav Brain Res 195, 239245.
  • Paylor, R., Tracy, R., Wehner, J. & Rudy, J.W. (1994) DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning. Behav Neurosci 108, 810817.
  • Petrovic, P., Kalisch, R., Singer, T. & Dolan, R.J. (2008) Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J Neurosci 28, 66076615.
  • Pezet, S. & Malcangio, M. (2004) Brain-derived neurotrophic factor as a drug target for CNS disorders. Expert Opin Ther Targets 8, 391399.
  • Picker, J.D., Yang, R., Ricceri, L. & Berger-Sweeney, J. (2006) An altered neonatal behavioral phenotype in Mecp2 mutant mice. Neuroreport 17, 541544.
  • Pierman, S., Tirelli, E., Douhard, Q., Baum, M.J. & Bakker, J. (2006) Male aromatase knockout mice acquire a conditioned place preference for cocaine but not for contact with an estrous female. Behav Brain Res 174, 6469.
  • Pijnenborg, G.H., Withaar, F.K., Bosch, R.J. & Brouwer, W.H. (2007) Impaired perception of negative emotional prosody in schizophrenia. Clin Neuropsychol 21, 762775.
  • Pomerantz, S.M., Nunez, A.A. & Bean, N.J. (1983) Female behavior is affected by male ultrasonic vocalizations in house mice. Physiol Behav 31, 9196.
  • Popik, P., Wrobel, M., Rygula, R., Bisaga, A. & Bespalov, A. (2003) Effects of memantine, an NMDA receptor antagonist, on place preference conditioned with drug and nondrug reinforces in mice. Behav Pharmacol 14, 237244.
  • Portfors, C.V. (2007) Types and functions of ultrasonic volcaizations in laboratory rats and mice. J Am Assoc Lab Anim Sci 46, 2834.
  • Reith, M.E. & Selmeci, G. (1992) Cocaine binding sites in mouse striatum, dopamine autoreceptors, and cocaine-induced locomotion. Pharmacol Biochem Behav 41, 227230.
  • Ren, Y., Johnson, M.T., Clemins, P., Darre, M., Glaeser, S.S., Osiejuk, T.S. & Out-Nyarko, E. (2009) A Framework for Bioacoustic Vocalization Analysis Using Hidden Markov Models Algorithms 2, 14101428.
  • Ruby, P. & Decety, J. (2004) How would you feel versus how do you think she would feel? A neuroimaging study of perspective-taking with social emotions. Journal of Cognitive Neuroscience 16, 988999.
  • Rupniak, N.M., Carlson, E.J., Webb, J.K., Harrison, T., Porsolt, R.D., Roux, S., de Felipe, C., Hunt, S.P., Oates, B. & Wheeldon, A. (2001) Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 12, 497508.
  • Rutherford, M.D., Baron-Cohen, S. & Wheelwright, S. (2002) Reading the mind in the voice: a study with normal adults and adults with Asperger syndrome and high functioning autism. J Autism Dev Disord 32, 189194.
  • Sadananda, M., Wöhr, M. & Schwarting, R.K.W. (2008) Playback of 22-kHz and 50-kHz ultrasonic vocalizations induces differential c-fos expression in rat brain. Neurosci Lett 435, 1723.
  • Sales, G.D. (1972) Ultrasound and mating behaviour in rodents with some observations on other behavioural situations. J Zool 168, 149164.
  • Sales, G. & Pye, D. (1974) Ultrasonic Communication by Animals. Chapman & Hall Ltd., London.
  • Scattoni, M., McFarlane, H., Zhodzishsky, V., Caldwell, H., Young, W., Ricceri, L. & Crawley, J. (2008a) Reduced ultrasonic vocalizations in vasopressin 1b knockout mice. Behav Brain Res 187, 371378.
  • Scattoni, M.L., Gandhy, S.U., Ricceri, L. & Crawley, J.N. (2008b) Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS ONE 3, e3067.
  • Schneirla, T.C. (1959) An evolutionary and developmental theory of biphasic processes underlying approach and withdrawal. In Jones, M.R. (ed), Nebraska Symposium on Motivation. University of Nebraska Press, Lincoln, pp. 142.
  • Scholten, M.R., Aleman, A. & Kahn, R.S. (2008) The processing of emotional prosody and semantics in schizophrenia: relationship to gender and IQ. Psychol Med 38, 887898.
  • Schwarting, R.K., Jegan, N. & Wöhr, M. (2007) Situational factors, conditions and individual variables which can determine ultrasonic vocalizations in male adult Wistar rats. Behav Brain Res 182, 208222.
  • Scott, J.P. (1966) Agonistic behavior of mice and rats: a review. Am Zool 6, 683701.
  • Sebeok, T.A. (1972) Perspectives in Zoosemiotics. Mouton, The Hague.
  • Sewell, G.D. (1969) Ultrasound in Small Mammals. Unpublished doctoral thesis, University of London, London.
  • Sewell, G.D. (1970) Ultrasonic communication in rodents. Nature 227, 410.
  • Shair, H.N., Brunelli, S.A., Masmela, J.R., Boone, E. & Hofer, M.A. (2003) Social, thermal, and temporal influences on isolation-induced and maternally potentiated ultrasonic vocalizations of rat pups. Dev Psychobiol 42, 206222.
  • Shriberg, L.D., Paul, R., McSweeny, J.L., Klin, A.M., Cohen, D.J. & Volkmar, F.R. (2001) Speech and prosody characteristics of adolescents and adults with high-functioning autism and Asperger syndrome. J Speech Lang Hear Res 44, 10971115.
  • Shu, W., Cho, J.Y., Jiang, Y., Zhang, M., Weisz, D., Elder, G.A., Schmeidler, J., De Gasperi, R., Sosa, M.A.G., Rabidou, D., Santucci, A.C., Perl, D., Morrisey, E. & Buxbaum, J.D. (2005) Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proceedings of the National Academy of Sciences of the United States of America 102, 96439648.
  • Silani, G., Bird, G., Brindley, R., Singer, T., Frith, C. & Frith, U. (2008) Levels of emotional awareness and autism: an fMRI study. Soc Neurosci 3, 97112.
  • Smith, A. (2009) The empathy imbalance hypothesis of autism: a theoretical approach to cognitive and emotional empathy in autistic development. Psychol Record 59, 273294.
  • Stiebler, I., Neulist, R., Fichtel, I. & Ehret, G. (1997) The auditory cortex of the house mouse: left-right differences, tonotopic organization and quantitative analysis of frequency representation. J Comp Physiol A Sens Neural Behav Physiol 181, 559571.
  • Tchernichovski, O., Mitra, P.P., Lints, T. & Nottebohm, F. (2001) Dynamics of the Vocal Imitation Process: How a Zebra Finch Learns Its Song. Science 291, 25642569.
  • Testa, J., Beatty, W., Gleason, A., Orbelo, D. & Ross, E. (2001) Impaired affective prosody in AD: Relationship to aphasic deficits and emotional behaviors. Neurology 57, 14741481.
  • Tzschentke, T.M. (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56, 613672.
  • Uekermann, J. & Daum, I. (2008) Social cognition in alcoholism: a link to prefrontal cortex dysfunction? Addiction 103, 726735.
  • Uekermann, J., Daum, I., Schlebusch, P. & Trenckmann, U. (2005) Processing of affective stimuli in alcoholism. Cortex 41, 189194.
  • Uekermann, J., Abdel-Hamid, M., Lehmkamper, C., Vollmoeller, W. & Daum, I. (2008) Perception of affective prosody in major depression: a link to executive functions? J Int Neuropsychol Soc 14, 552561.
  • van Ree, J.M., Gerrits, M.A. & Vanderschuren, L.J. (1999) Opioids, reward and addiction: an encounter of biology, psychology, and medicine. Pharmacol Rev 51, 341396.
  • Vanderschuren, L.J., Stein, E.A., Wiegant, V.M. & Van Ree, J.M. (1995) Social play alters regional brain opioid receptor binding in juvenile rats. Brain Res 680, 148156.
  • Wan, M.W., Penketh, V., Salmon, M.P. & Abel, K.M. (2008) Content and style of speech from mothers with schizophrenia towards their infants. Psychiatry Res 159, 109114.
  • Wang, H., Liang, S., Burgdorf, J., Wess, J. & Yeomans, J. (2008) Ultrasonic vocalizations induced by sex and amphetamine in M2, M4, M5 muscarinic and D2 dopamine receptor knockout mice. PLoS ONE [Electronic Resource] 3, e1893.
  • Weller, A., Tsitolovskya, L., Gispan, I.H. & Rabinovitz, S. (2001) Examining the role of cholecystokinin in appetitive learning in the infant rat. Peptides 22, 13171323.
  • White, N.R., Prasad, M., Barfield, R.J. & Nyby, J.G. (1998) 40- and 70-kHz vocalizations of mice (Mus musculus) during copulation. Physiol Behav 63, 467473.
  • Whitney, G.D. (1969) Vocalization of mice: a single genetic unit effect. J Hered 60, 337340.
  • Whitney, G. & Nyby, J. (1979) Cues that elicit ultrasounds from adult male mice. Am Zool 19, 457463.
  • Whitney, G. & Nyby, J. (1983) Sound communication among adults. In Willot, J.F. (ed),The Auditory Psychology of the Mouse. Charles C Thomas, Springfield, pp. 98129.
  • Winslow, J.T. & Insel, T.R. (2002) The social deficits of the oxytocin knockout mouse. Neuropeptides 36, 221229.
  • Winslow, J.T., Hearn, E.F., Ferguson, J., Young, L.J., Matzuk, M.M. & Insel, T.R. (2000) Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 37, 145155.
  • Winter, C.A. (1965) The physiology and pharmacology of pain. In de Stevens, G. (ed), Analgesics. Academic, New York.
  • Wöhr, M. & Schwarting, R.K. (2009) Ultrasonic communication in rats: effects of morphine and naloxone on vocal and behavioral responses to playback of 50-khz vocalizations. Pharmacol Biochem Behav 94, 285295.
  • Wöhr, M., Dahlhoff, M., Wolf, E., Holsboer, F., Schwarting, R.K. & Wotjak, C.T. (2008) Effects of genetic background, gender, and early environmental factors on isolation-induced ultrasonic calling in mouse pups: an embryo-transfer study. Behav Genet 38, 579595.
  • Wolf, J.M., Tanaka, J.W., Klaiman, C., Cockburn, J., Herlihy, L., Brown, C., South, M., McPartland, J., Kaiser, M.D., Phillips, R. & Schultz, R.T. (2008) Specific impairment of face-processing abilities in children with autism spectrum disorder using the Let's Face It! skills battery. Autism Res 1, 329340.
  • Yeomans, J.S., Takeuchi, J., Baptista, M., Flynn, D.D., Lepik, K., Nobrega, J., Fulton, J. & Ralph, M.R. (2000) Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells. J Neurosci 20, 88618867.
  • Yeomans, J., Forster, G. & Blaha, C. (2001) M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation. Life Sci 68, 24492456.
  • Yip, J.T. & Lee, T.M. (2006) Selective impairment of sadness and disgust recognition in abstinent ecstasy users. Neuropsychologia 44, 959965.
  • Young, P.T. (1959) The role of affective processes in learning and motivation. Psychol Rev 66, 104125.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Prosody
  4. Genetics
  5. Future directions
  6. Summary
  7. References
  8. Acknowledgments

The authors wish to thank Jan Van Santen and Lois Black of Oregon Health and Science University for communicating their insights to prosodic communication. We also want to acknowledge the Waisman Center at the University of Wisconsin for support (P30 HD03352). This work was supported by R01 funding from the National Institute of Drug Abuse (DA022543).