Frequency-modulated 50 kHz ultrasonic vocalizations: a tool for uncovering the molecular substrates of positive affect

doi:10.1016/j.neubiorev.2010.11.011

Neuroscience & Biobehavioral Reviews

Volume 35, Issue 9, October 2011, Pages 1831-1836

https://doi.org/10.1016/j.neubiorev.2010.11.011 Get rights and content

Abstract

The evidence that frequency modulated (FM) 50 kHz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. Positive emotional states in humans are measured by facial-vocal displays (e.g., Duchenne smiling and laughter), approach behavior, and subjective self-report of feeling states. In laboratory animals, only facial-vocal displays, along with approach behavior can be measured. FM 50 kHz USVs are uniquely elevated by hedonic stimuli and suppressed by aversive stimuli. Rates of FM 50 kHz USVs are positively correlated to the rewarding value of the eliciting stimulus. Additionally, playbacks of these vocalizations are rewarding. The neural and pharmacological substrates of 50 kHz USVs are consistent with those of human positive affective states. By experimentally eliciting FM 50 kHz USVs, the novel molecular underpinning of positive affect can be elucidated and may be similar to those in humans. In humans, positive emotional states confer resilience to depression and anxiety, as well as promote overall health. Using rough-and-tumble play induced hedonic USVs, we have identified insulin like growth factor I and the NR2B subunit of the NMDA receptor as playing a functional role in positive affective states. From this research, we have developed a promising new class of antidepressants that is entering phase II clinical trials for the treatment of depression.

Section snippets

Measuring positive affective states in humans

In humans, socializing with friends or romantic partners elicits the highest levels of positive affect (Csikszentmihalyi and Hunter, 2003, Stone et al., 2006). Experimental studies that elicit positive affective states generally use social positive affective stimuli (i.e., positive feedback, giving a small gift, or watching a video tape eliciting positive affective state). Positive affective states that are elicited in an experimental setting by these social stimuli have been shown to increase

Measuring positive affective states in laboratory animals

In order to establish that an animal behavior reflects a positive affective state, several criteria must be met. In humans, positive affective states are measured primarily via subjective self-report and behaviorally by facial/vocal displays such as felt- or Duchenne-smiling (Ekman et al., 1990). Therefore, in laboratory animal experiments, where we can rely only on empirical observations with no possibility of semantic reports of subjective states, a positive affective state should be

Using hedonic USVs to uncover the novel molecular substrates of positive affect

Genes specific to positive affective states can be uncovered by examining transcripts that are upregulated by hedonic play, but not aversive social defeat (Burgdorf et al., 2010a). To this aim, we have developed an in-house fabricated focused microarray platform, which can detect families of genes that are specifically upregulated following hedonic rough-and-tumble play when coupled with appropriate bioinformatics tools, These mRNA changes are corroborated by quantitative qrtPCR and

Conclusions

Affective neuroscience approaches to brain emotional systems provide convergent methodologies to decipher molecular mechanisms for the generation of a variety of positive affective states. We are confident that indices such as 50 kHz USVs express positive emotional states because all of the brain sites localized in SEEKING circuits that generate these sounds also sustain self-stimulation behavior (Burgdorf et al., 2007), a critical criterion for positive affect processes of the brain. The

Acknowledgements

This work was supported by Hope for Depression Research Foundation (New York, NY) and The Ralph and Miriam Falk Foundation (Chicago, IL).

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The subjective nature of human emotions makes them uniquely challenging to investigate in preclinical models. While behavioral assays in rodents aim to evaluate affect (i.e., anxiety, hypervigilance), they often lack ethological validity. Playback of negatively valenced 22-kHz ultrasonic vocalizations (USVs) in rats shows promise as a translational tool to investigate affective processing. Much like how human facial expressions can communicate internal states, rats emit 22-kHz USVs that similarly convey negative affective states to conspecifics indicating possible threat. 22-kHz USV playback elicits avoidance and hypervigilant behaviors, and recruit brain regions comparable to those seen in human brains evoked by viewing fearful faces. Indeed, 22-kHz playback alters neural activity in brain regions associated with negative valence systems (i.e., amygdala, bed nucleus of the stria terminalis, periaqueductal gray) alongside increases in behaviors typically associated with anxiety. Here, we present evidence from the literature that supports leveraging 22-kHz USV playback in rat preclinical models to obtain clinically relevant and translational findings to identify the neural underpinnings of affective processing and neuropathological dysfunction.
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Many rodent species emit and detect vocalizations in the ultrasonic range. Rats use three classes of ultrasonic vocalizations depending on developmental stage, experience and the behavioral situation. Calls from one class emitted by juvenile and adult rats, the so-called 50-kHz calls, are typical for appetitive and social situations. This review provides a brief historical account on the introduction of 50-kHz calls in behavioral research followed by a survey of their scientific applications focusing on the last five years, where 50-kHz publications reached a climax. Then, specific methodological challenges will be addressed, like how to measure and report 50-kHz USV, the problem of assignment of acoustic signals to a specific sender in a social situation, and individual variability in call propensity. Finally, the intricacy of interpreting 50-kHz results will be discussed focusing on the most prevalent ones, namely as communicative signals and/or readouts of the sender’s emotional status.
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ReviewFrequency-modulated 50 kHz ultrasonic vocalizations: a tool for uncovering the molecular substrates of positive affect

Abstract

Section snippets

Measuring positive affective states in humans

Measuring positive affective states in laboratory animals

Using hedonic USVs to uncover the novel molecular substrates of positive affect

Conclusions

Acknowledgements

Brain Cogn.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Neuroscience

Physiol. Behav.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

J. Theor. Biol.

Eur. J. Pharmacol.

Biol. Psychiatry

Brain Res. Rev.

Pain

Eur. Neuropsychopharmacol.

Behav. Brain Res.

Brain Res. Bull.

Pharmacol. Ther.

Neuroscience

Neuroscience

Behav. Brain Res.

Physiol. Behav.

Brain Res.

Trends Pharmacol. Sci.

Behav. Brain Res.

Brain Res.

Trends Pharmacol. Sci.

Neuropsychopharmacology

Enhanced cortical extracellular levels of cholecystokinin-like material in a model of anticipation of social defeat in the rat

J. Neurosci.

Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin

Mol. Psychiatry.

Ultrasounds in small rodents: arousal-produced and arousal-producing

Dev. Psychobiol.

Antipredator defensive behaviors in a visible burrow system

J. Comp. Psychol.

Affective neuroscience of pleasure: reward in humans and animals

Psychopharmacology

Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion

Proc. Natl. Acad. Sci. U.S.A.

Rodent ultrasonic short calls: locomotion, biomechanics, and communication

J. Comp. Psychol.

The Runner's high: opioidergic mechanisms in the human brain

Cereb. Cortex

Anticipation of rewarding electrical brain stimulation evokes ultrasonic vocalization in rats

Behav. Neurosci.

Nucleus accumbens amphetamine microinjections unconditionally elicit 50-kHz ultrasonic vocalizations in rats

Behav. Neurosci.

Evaluation of rat ultrasonic vocalizations as predictors of the conditioned aversive effects of drugs

Psychopharmacology

Ultrasonic vocalizations of rats (Rattus norvegicus) during mating, play, and aggression: behavioral concomitants, relationship to reward, and self-administration of playback

J. Comp. Psychol.

Breeding for 50-kHz positive affective vocalization in rats

Behav. Genet.

Review
Frequency-modulated 50 kHz ultrasonic vocalizations: a tool for uncovering the molecular substrates of positive affect