NIMH Non-Human Primate Research Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, uSA
Alarm calls; Crying; Isolation calls; Separation calls; ultrasonic vocalizations
Mammalian vocalizations are the product of respiratory and laryngeal activities under the direct control of brain stem cranial and spinal motor neurons and modulated by higher brain processes (Miczek et al. 1995; Newman 2007). Distress vocalizations are sounds produced in the presence of painful, stressful, or threatening stimuli. Vocalizations are a particularly attractive candidate for psycho-pharmacological research because they represent species specific and ethologically relevant behaviors spontaneously expressed in response to unique provocation. Vocalizations offer the further promise of unique informational content about the emotional state of the subject. Finally, there is evidence that the form, contexts, and neural processes which modulate distress vocalizations are highly conserved between species (Newman 2007). This makes them a particularly attractive candidate for translating findings from animal models to human clinical conditions.
Pharmacological studies of distress vocalizations can be predominantly clustered according to the maturity of the subjects examined - infant or adult.
Infant distress vocalization: The production of vocalizations by infant mammals during parental separations has been detected in virtually every known mammalian species including humans (Newman 2007). Rat and mouse infant vocalizations have been the most vigorously studied by psychopharmacologists and are expressed in the ► ultrasonic frequency range. Drug effects on the vocalization by several nonhuman primate species have also been examined including rhesus, squirrel, and marmoset monkeys. Across species, infant vocalizations share remarkable structural as well as contextual similarities (Newman 2007) (Fig. 1).
Adult distress vocalization: Adult animals also produce intense vocalizations when provoked by painful, threatening, or stressful stimuli or during drug withdrawal.
Like infant vocalizations, these too share remarkable structural similarities between species, and in rodents they are also predominantly ultrasonic (Miczek et al. 1995; Sanchez 2003).
Vocalizations in both age groups have been proposed to reflect emotional states of fear or anxiety. Consequently, they have been primarily the target of research related to ► anxiolytic drugs and/or neural substrates of emotional behavior. The separation vocalizations of infant animals have also been proposed to reflect frustration of attachment bonds and consequently a further focus of pharmacological research has examined neural processes associated with the formation and maintenance of social bonds.
In the ensuing essay, we will focus our discussion on the ultrasonic vocalizations of rodents since the preponderance of pharmacological study has likewise been examined primarily in rodents. Nevertheless, the basic principles of measurement and many of the pharmacological findings have been replicated in nonhuman primates (Levine and Mody 2003; Winslow et al. 2007).
Vocalizations are typically audio recorded and then defined and quantified using sound ► spectrographic techniques which also allow automated detection for some call types. For rodent species, specialized recording equipment capable of detecting ultrasonic frequency ranges is required and commercial systems are available (see Hofer et al. (2002) for an excellent guide).
Rodent infants emit ultrasonic (30-50 kHz in rat and 50-80 kHz) vocalizations ranging from 100 to 500 ms in duration virtually from the day after birth to the time of weaning. It is notable that the rate and intensity of calling varies systematically by age. Separation of a pup from its home cage, littermates, and dam into a novel test chamber elicits high rates of ultrasonic calls, and is the most frequently used eliciting stimulus in pharmacological studies.
Adult rats produce "distress" ultrasonic vocalizations in the 20-30 and 50-70 kHz range during encounters wherein they are attacked or threatened by a conspecific. 22 kHz calls are also emitted by rats in the presence of painful or stressful (e.g., startle or air-puff stimuli) stimuli as well as during opioid and cocaine withdrawal. Taken together these results suggest that distress vocalizations, particularly the 22 kHz of rats may convey an anxious or fearful emotional state common to multiple contexts. Adult mice also emit ultrasonic vocalizations; however, so far these have been detected only in reproductive encounters and not, notably, in the stressful or aversive conditions typical of rats.
Distress Vocalization. Fig. 1. Depicts distress calls expressed by infant, juvenile, and adult animals including (a) the isolation peep call of the juvenile squirrel monkey; (b) the coo call of the macaque monkey (Japanese); (c) the mouse pup ultrasonic separation call; (d) the rat pup ultrasonic separation call; and (e) the 22 kHz ultrasonic distress call of the adult rat. The call shows remarkable similarities in form. (Adapted from Ceugniet and Izumi 2004; Miczek et al. 1995; and www.avisoft.com/rat.)
Measurements of duration of ultrasonic vocalization, inter-ultrasonic vocalization interval, bout structure, and detailed acoustic analysis of calls have been performed, but have not been systematically studied in relation to eliciting conditions, regulation by sensory cues, or neural control though initial efforts suggest important information may be available in these parameters (Scattoni et al. 2008).
Developmental changes in vocalization: Infant vocalizations show a pronounced change in the pattern of calling as animals mature. Ultrasonic vocalization responses of infant rodents follow a fairly predictable developmental pattern. The first ultrasonic vocalization response to isolation occurs in a day or two after birth at a moderate rate at typical ambient temperatures (32-35° C), then rises to a peak in the first week at about 100/min, finally beginning a gradual decline until approximately the same age they obtain ► homeothermy, at which point few or ultrasonic vocalizations may be detected within a 10 min separation test. Conversely, adult-type vocalizations in appropriate contexts once established in puberty remain remarkably stable though not without variability between individuals.
Role of thermoregulation: The ambient temperature of the test chamber is the most easily manipulated regulator of ultrasonic vocalization rate in rat and mouse pups during their first two weeks of postnatal life (Hofer 2002). Ultrasonic vocalization rates expressed by isolated pups can be systematically varied from 10 or less calls per minute at typical ambient temperatures up to 200 calls/ min in cooler environments. The relationship between ultrasonic vocalization and temperature has led some to hypothesize that ultrasonic vocalization emissions might also play a role in pups' physiological thermoregulatory capacity (Blumberg and Alberts 1991). According to this view ultrasonic vocalization could be considered, at least in part, a byproduct of thermoregulatory physiology rather than an affective expression in a communicative system (Blumberg and Alberts 1991). Indeed, correlations have been found between ultrasonic vocalization production and thermoregulatory and cardiovascular changes. Similar proposals have been offered to account for adult rodent ultrasonic vocalizations. Nevertheless, a clear physiological role for ultrasonic vocalization in thermoregulation has yet to be demonstrated except perhaps during recovery from severe hypothermia (Hofer and Shair 1992). In contrast, there are several lines of evidence that the physiological changes involved in the act of ultrasonic vocalization emission do not play a functionally significant role in the thermoregulation of young rats, at least under typical test conditions (Hofer 2002).
Species and strain differences: As noted earlier, while there appear to be many similarities between species in context, form, and neural processes, there are nevertheless important differences between species that are evident -not the least being the frequency range within which the calls are expressed. In addition, there are differences in the sensitivity of the rodent species to the modulation of calling by social stimuli (e.g., comforting upon return of the mother to her infant) or the type and intensity of provocation by some stimuli in adult animals (Hofer 2002). These are even more evident in the wide range of differences in the rate of calling that can be obtained when comparing between various strains of mice used in genetic modeling research (Wohr et al. 2008).
Pharmacological studies of distress vocalizations have been undertaken for various reasons, from aiding the development of animal models of clinical anxiety to demonstrating the functional efficacy of a system in development, or to examining the neural processes related to the formation and maintenance of social attachment -particularly infant-mother bonds.
Infant distress vocalizations have proven to be remarkably sensitive to both the anxiolytic-like effects of GABAergic, serotonergic, and glutamatergic receptor subtype selective ► ligands as well as the ► anxiogenic-like effects often reported for ligands with complementary actions at the same or related receptor subtypes (Winslow and Insel 1991). Thus, for example, GABA-A agonists such as ► diazepam reduce vocalizations while antagonists such as pentylenetetrazol increase vocalizations (Miczek et al. 1995). Conversely glutamate receptor antagonists such as MK801 decrease while agonists such as NMDA increase calling (Winslow et al. 1990). Similarly, serotoninergic drugs with putative anxiolytic properties such as the 5HT-1A receptor agonist ► buspirone reduce calling in infant rats while 5HT-1B receptor agonists appear to increase call rates, although the dose relationship may be complex (Winslow and Insel 1991). Similarly, studies of adult distress vocalizations indicate comparable predictive validity for GABAergic, glutama-tergic, and serotonergic ligands as anxiolytic or anxio-genic compounds depending on the subtype of the receptor affected (Sanchez 2003; Takahashi et al. 2008).
A number of systems have been proposed to have important roles in the formation and maintenance of attachment bonds between social animals. Prominent among these are the opioid system because social attachment has some similarities to drug dependence. Oxytocin and vasopressin have also been implicated in the formation and maintenance of mother-infant bonds as well as between adults with monogamous mating strategies. Studies of the effects of ligands active in these systems have generally demonstrated that distress vocalizations provoked by maternal loss are predictably modulated. For example, oxytocin or ► morphine administration effectively quiets infant mice, rats, and young monkeys separated from their social companions.
Distress vocalizations are a prominent feature of withdrawal from chronic administration of a variety of pharmacological drugs of dependence including opiates, benzodiazepines, ► alcohol, and ► psychomotor stimulants (Covington and Miczek 2003). While distress vocalizations during withdrawal are evident in a variety of species, systematic study has been thus far limited to rats. These few studies have demonstrated that the rate of calling is independent of an audience and directly related to key parameters of chronic administration such as how much drug is administered, for how long and whether the drug is self-administered or administered by a researcher (Covington and Miczek 2003).
► Animal Models for Psychiatric States
► Anxiety: Animal Models
► Autism: Animal Models
► Emotion and Mood
► Excitatory Amino Acids and their Antagonists
► Inverse Agonists
► Phenotyping of Behavioral Characteristics
► SNRI Antidepressants
► Social Stress
► SSRIs and Related Compounds
► Translational Research
► Traumatic Stress (Anxiety) Disorder
Blumberg MS, Alberts JR (1991) On the significance of similarities between ultrasonic vocalizations of infant and adult rats. Neurosci Biobehav Rev 15:383-390 Ceugniet M, Izumi A (2004) Vocal individual discrimination in Japanese monkeys. Primates 45:119-128 Covington HE III, Miczek KA (2003) Vocalizations during withdrawal from opiates and cocaine: possible expressions of affective distress. Eur J Pharmacol 467:1-13 Hofer MA (2002) Unexplained infant crying: an evolutionary perspective. Acta Paediatr 91:491-496 Hofer MA, Shair HN (1992) Ultrasonic vocalizations by rat pups during recovery from deep hypothermia. Dev Psychobiology 25 (7):511-528
Hofer MA, Shair HN, Brunelli SA (2002) Ultrasonic vocalizations in rat and mouse pups. Curr Protoc Neurosci Chapter 8:Unit 8.14 Levine S, Mody T (2003) The long-term psychobiological consequences of intermittent postnatal separation in the squirrel monkey. Neurosci Biobehav Rev 27:83-89 Miczek KA, Weerts EM, Vivian JA, Barros HM (1995) Aggression, anxiety and vocalizations in animals: GABAA and 5-HT anxiolytics. Psycho-pharmacology (Berl) 121:38-56 Newman JD (2007) Neural circuits underlying crying and cry responding in mammals. Behav Brain Res 182:155-165 Sanchez C (2003) Stress-induced vocalisation in adult animals: a valid model of anxiety? Eur J Pharmacol 463:133-143 Scattoni ML, Gandhy SU, Ricceri L, Crawley JN (2008) Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS One 3:e3067 Takahashi A, Yap JJ, Bohager DZ, Faccidomo S, Clayton T, Cook JM, Miczek KA (2008) Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups. Psychopharmacology (Berl) 204:61-71 Winslow JT, Insel TR (1991) Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists. Psychopharmacology (Berl) 105:513-520
Winslow JT, Insel TR, Trullas R, Skolnick P (1990) Rat pup isolation calls are reduced by functional antagonists of the NMDA receptor complex. Eur J Pharmacol 190:11-21 Winslow JT, Noble PL, Davis M (2007) Modulation of fear-potentiated startle and vocalizations in juvenile rhesus monkeys by morphine, diazepam, and buspirone. Biol Psychiatry 61:389-395 Wohr M, Dahlhoff M, Wolf E, Holsboer F, Schwarting RK, Wotjak CT (2008) Effects of genetic background, gender, and early environmental factors on isolation-induced ultrasonic calling in mouse pups: an embryo-transfer study. Behav Genet 38:579-595
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