Biological Functions of Rat Ultrasonic Vocalizations, Arousal Mechanisms, and Call Initiation

Abstract

This review summarizes all reported and suspected functions of ultrasonic vocalizations in infant and adult rats. The review leads to the conclusion that all types of ultrasonic vocalizations subserving all functions are vocal expressions of emotional arousal initiated by the activity of the reticular core of the brainstem. The emotional arousal is dichotomic in nature and is initiated by two opposite-in-function ascending reticular systems that are separate from the cognitive reticular activating system. The mesolimbic cholinergic system initiates the aversive state of anxiety with concomitant emission of 22 kHz calls, while the mesolimbic dopaminergic system initiates the appetitive state of hedonia with concomitant emission of 50 kHz vocalizations. These two mutually exclusive arousal systems prepare the animal for two different behavioral outcomes. The transition from broadband infant isolation calls to the well-structured adult types of vocalizations is explained, and the social importance of adult rat vocal communication is emphasized. The association of 22 kHz and 50 kHz vocalizations with aversive and appetitive states, respectively, was utilized in numerous quantitatively measured preclinical models of physiological, psychological, neurological, neuropsychiatric, and neurodevelopmental investigations. The present review should help in understanding and the interpretation of these models in biomedical research.

Chronic Fentanyl Self-Administration Generates a Shift toward Negative Affect in Rats during Drug Use

“…Thereafter, 22 kHz calls dominate the maintenance phase, increasing whenever drug level falls [37]. Cocaine generates a positive affect upon first exposure to SA [16], along with motoric activation and emotional arousal, which is the driving force for the emission of USVs [8]. This does not appear to be the case for fentanyl SA, as initial exposure to fentanyl SA generated neither positive nor negative affect in the present study.…”

“…That increase in negative calls plus the lack of major changes in the call rates of either frequency at ABS highlight the presence of negative affect during drug use after repeated exposure to the drug, not just once the drug has left the body and withdrawal sets in. The mix of both 22 and 50 kHz calls during the 6 h ABS session may reflect fluctuations between a negative affective state associated with opioid withdrawal [6] and a positive affective state associated with anticipation of drug for the 31st consecutive day, since 50 kHz calls can indicate an anticipatory state [8,33,34].…”

“…This suggests that chronic fentanyl SA involves aversive effects, despite the presence of reinforcement and cardinal signs of addiction. Multiple ascending pathways originating in the brainstem are responsible for the generation of emotional arousal, including the ventral dopaminergic system originating in the ventral tegmental area (VTA) [8], a pathway strongly implicated in the rewarding effects of both opioids and stimulants. In the case of stimulants such as cocaine, the lateral habenula has been implicated in playing a critical role in the regulation of negatively motivated behaviors by targeting midbrain neuromodulatory systems such as the dopaminergic pathway projecting from the VTA [41,42].…”

“…Due to their predictable occurrence in response to aversive situations, 22 kHz calls are considered representative of a negative affective state and are generated during common behavioral situations such as exposure to predators [3], unfamiliar touch [4], drug withdrawal [5,6], and exposure to pain such as foot shock [7]. Conversely, 50 kHz calls are reliably emitted during situations involving the anticipation of potential reward [8,9], social contact [10], electrostimulation of mesolimbic sites supporting self-stimulation [11], and the administration of addictive drugs [12,13]. Therefore, 50 kHz calls are representative of an appetitive, hedonic behavioral state associated with positive affect [9,10].…”

Individual Differences in Conditioned Fear and Extinction in Female Rats

“…The existing literature also shows inconsistent sex differences in freezing during fear extinction, with some studies reporting enhanced fear extinction in females compared with males and other studies finding the opposite ( Maren et al, 1994 ; Baran et al, 2009 ; Milad et al, 2009 ; Fenton et al, 2014 ; Velasco et al, 2019 ; Day and Stevenson, 2020 ). USVs are another quantitative measure of rodent affective states ( Knutson et al, 2002 ; Sangiamo et al, 2020 ; Brudzynski, 2021 ), and are increasingly being used to model affective disorders in rodents ( Burgdorf et al, 2020 ). Long (>300 ms) vocalizations around 22 kHz (ranging from 18 to 32 kHz) are generally emitted during distressing situations including fear conditioning ( Borta et al, 2006 ; Litvin et al, 2007 ), whereas shorter (20–80 ms) vocalizations around 50 kHz (32–70 kHz) are produced in a variety of rewarding conditions such as positive social interactions and administration of addictive drugs ( Portfors, 2007 ; Schwarting and Wöhr, 2012 ; Brudzynski, 2015 , 2021 ).…”