Date of Award
Doctor of Philosophy (PhD)
Interdepartmental Neuroscience Program
Abstract The proper development of infant mammals depends on infant vocalization. Infants vocalize (i.e., cry) when isolated from their caregivers, attracting their attention to receive nurture. Impaired vocal behavior can lead to maternal neglect and even death in some species. Similar to humans and other mammals, infant mice vocalize upon isolation from their nest and decrease vocalizations when reunited with their mother or littermates. Mouse pups vocalize above the human audible range, emitting ultrasonic vocalizations (USV). My thesis investigated the effects of the imprinted gene, Magel2, on mouse vocal behavior (Chapter 2; published in Genes, Brain, and Behavior) and also identified a population of neurons in the hypothalamus that modulate vocal behavior (Chapter 3; unpublished). Magel2 (or MAGEL2 in humans) is a paternal imprint gene and its loss of function is associated with atypical behaviors seen in autism spectrum disorders and in Prader-Willi Syndrome. In Chapter 2, I report the study of the emission of ultrasonic vocalizations by Magel2 deficient pups during their early postnatal development. I recorded and analyzed vocalizations from Magel2 deficient pups and their wildtype littermates during isolation from the home nest at postnatal days 6-12. I describe my findings showing that Magel2 deficient pups present a lower rate of vocalizations and altered vocal repertoire compared to wildtype littermates. Moreover, these results correlate with altered behavior of the dam towards their own pups: dams prefer to retrieve their wildtype offspring compared to their Magel2 deficient offspring. These results suggest that Magel2 affects the expression of infant vocalizations and also modulates the expression of maternal behaviors. In Chapter 3, I describe my discovery of a population of neurons in the mammalian hypothalamus that modulate the emission of ultrasonic vocalizations in mouse pups. The brain opioid theory of social attachment postulates that pups release opioids in the brain during caretaking behaviors, which reinforces the attachment bond between pups and caretakers. From the three main receptors known to bind different types of endogenous opioids, μ-opioid receptors (ORPM1) are thought to be important in the modulation of attachment behaviors and, consequently, emission of vocalizations. Whether endogenous opioids act on ORPM1-expressing cells to modulate vocalizations is unknow. Since the opioid with highest affinity for ORPM1 is β-endorphin, I determined the contribution of neurons that produce β-endorphin—POMC neurons—in infant vocalizations. Using genetic, chemogenomic, and pharmacogenetic approaches, my results show that mice deficient for β-endorphin vocalize more than controls, an effect that is mimicked by a pharmacological blocker of opioid receptors, naloxone. Importantly, naloxone fails to increase vocalizations in β-endorphin deficient pups. Moreover, using chemogenetics, activation of POMC neurons in the hypothalamus suppresses the emission of vocalizations, while ablation of these neurons increased the number of vocalizations. Finally, I show that activation of POMC neurons in mice deficient for the Orpm1 does not suppress the emission of vocalizations. Together, the results in Chapter 3 suggest that the emission of infant vocalizations is modulated by POMC neurons in the hypothalamus via the release of beta-endorphin that signals in downstream mu-opioid receptors. In sum, this dissertation reports novel findings on the effect of the Magel2 gene and of hypothalamic POMC neurons in the modulation of infant vocalization. As we learn more about the physiological and neuronal responses to distress that occurs in infants, we will more accurately understand the mechanisms involved in the affective emotional states that contribute to the normal and pathological development of infants.
Bosque Ortiz, Gabriela M., "Magel2 and Hypothalamic POMC Neuron Modulation of Infant Mice Isolation-Induced Vocalizations" (2022). Yale Graduate School of Arts and Sciences Dissertations. 562.