br Introduction The offspring of rodents

Introduction The offspring of rodents emit vocalizations when isolated from their dam. The majority of vocalizations by rat pups are in the ultrasonic band frequency of 30–50 kHz (Insel et al., 1986). Maternal separation-induced ultrasonic vocalizations are believed to represent distress signals from the pup. This assumption is supported by the observation that WM-2474 the number of vocalizations can be attenuated by the administration of anxiolytics and antidepressants (Olivier et al., 1998a, Olivier et al., 1998b, Branchi et al., 2001). Previous studies have shown that the number of vocalizations from isolated pups is modulated by changes in environmental conditions such as ambient temperature, tactile stimuli and odors normally provided by the dam. Low ambient temperature (18 °C) increased callings by isolated rat pups, whereas at 37 °C, which was close to the temperature of the nest in which the dam and littermates lived, callings decreased (Olivier et al., 1998a, Olivier et al., 1998b). The increased callings of an isolated pup at room temperature were significantly reduced in the presence of the anesthetized dam (Shair et al., 1999). However, exactly how environmental factors affect the neuronal mechanisms controlling maternal separation-induced ultrasonic vocalizations is unclear. Corticotropin-releasing factor (CRF) is a hypothalamic-releasing peptide that activates the hypothalamic–pituitary–adrenal (HPA) axis and plays a pivotal role in anxiety- and distress-induced endocrine and behavioral responses (Vale et al., 1981, Heinrichs and Koob, 2004). Central administration of CRF to rats induces anxiogenic behaviors in an elevated plus-maze test (Dunn and Berridge, 1990, Heinrichs and Koob, 2004). In contrast, blockade of the CRF1 receptor reduces anxiety and stress responses in an elevated plus-maze test and a social interaction test (Smith et al., 1998, Timpl et al., 1998, Chaki et al., 2004, Gehlert et al., 2005). A CRF1 receptor antagonist decreases the number of ultrasonic vocalizations induced by maternal separation under high-stress (low ambient temperature) condition (Kehne et al., 2000, Iijima and Chaki, 2005). These reports suggest that endogenous CRF modulates the emotional state by activating CRF1 receptor. The number of vocalizations elicited by maternal separation was thus expected to be exaggerated with administration of CRF (Insel and Harbaugh, 1989, Harvey and Hennessy, 1995). However, exogenous CRF did not increase the number of ultrasonic vocalizations induced by maternal separation in both high-stress (low ambient temperature) and low-stress (high ambient temperature) conditions (Insel and Harbaugh, 1989, Harvey and Hennessy, 1995, Dirks et al., 2002). Harvey and Hennessy (1995) thought that endogenous CRF was involved in the generation of a high number of vocalizations under high-stress conditions, but might be insufficient to generate ultrasonic vocalizations under low-stress conditions. How CRF influences the generation of maternal separation-induced ultrasonic vocalization under low-stress conditions thus remains unclear.