Neurotensin inversely modulates maternal aggression

Abstract

Neurotensin (NT) is a versatile neuropeptide involved in analgesia, hypothermia, and schizophrenia. Although NT is released from and acts upon brain regions involved in social behaviors, it has not been linked to a social behavior. We previously selected mice for high maternal aggression (maternal defense), an important social behavior that protects offspring, and found significantly lower NT expression in the CNS of highly protective females. Our current study directly tested NT's role in maternal defense. Intracerebroventricular (icv) injections of NT significantly impaired defense in terms of time aggressive and number of attacks at all doses tested (0.05, 0.1, 1.0, and 3.0 μg). Other maternal behaviors, including pup retrieval, were unaltered following NT injections (0.05 μg) relative to vehicle, suggesting specificity of NT action on defense. Further, icv injections of the NT receptor 1 (NT1) antagonist, SR 48692 (30 μg), significantly elevated maternal aggression in terms of time aggressive and attack number. To understand where NT may regulate aggression, we examined Fos following injection of either 0.1 μg NT or vehicle. 13 of 26 brain regions examined exhibited significant Fos increases with NT, including regions expressing NT1 and previously implicated in maternal aggression, such as lateral septum, bed nucleus of stria terminalis, paraventricular nucleus, and central amygdala. Together, our results indicate that NT inversely regulates maternal aggression and provide the first direct evidence that lowering of NT signaling can be a mechanism for maternal aggression. To our knowledge, this is the first study to directly link NT to a social behavior. Keywordsfight; flight; maternal aggression; maternal defense; lactation; mice Neurotensin (NT) is a versatile neuropeptide that plays a role in analgesia (Dubuc et al., 1999, Sarret et al., 2005, hypothermia (Nemeroff et al., 1977, Martin et al., 1980, Remaury et al., 2002, and schizophrenia (Nemeroff, 1986, Kinkead and. NT acts most commonly via either NT receptor 1 (NT1) or receptor 2 (NT2) (Tanaka et al., 1990, Richard et al., 2001, Sarret et al., 2002, but it can also act via NT receptor 3, a sortilin receptor that internalizes the ligand (Mazella, 2001). NT and its receptors are highly conserved among mammals (Dobner, 2005). Although NT is expressed in and acts upon a number of areas critical for social behavior, including nucleus accumbens, lateral septum (LS), bed nucleus of stria terminalis (BNST), preoptic area, amygdala, and periaqueductal gray (Boudin et al., 1996, Binder et al., 2001a, Sarret et al., 2003, it has received almost no research attention regarding Corresponding Author: Stephen C. Gammie, 1117 W. Johnson St., Madison, WI 53706, Telephone: (608) Fax: (608) 262-9083, E-mail: scgammie@wisc.edu. Section Editor: Joan Morrell Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscrip...

Functional, anatomical, and neurochemical differentiation of medial preoptic area subregions in relation to maternal behavior in the mouse

“…Not only VTA but also other brain areas might respond to these peptides during maternal behavior. The responsiveness of neurotensin is altered in various brain areas during the postpartum period (Gammie et al, 2009(Gammie et al, , 2012Scotti et al, 2011), and vasopressin and oxytocin release from magnocellular neurons in the periventricular nucleus was inhibited by the receptor antagonism of neurokinin B (Haley and Flynn, 2008). The direct role of these peptides in performance of maternal behavior, however, has not been suggested by observations of genetic mutant mice with deletion of these peptides or their receptors (Wynick al., 1998;Dobner et al, 2001;Jacoby et al, 2002;Kung et al, 2004), and the distribution of c-Fos-ir neurons expressing these peptides overlapped with, but is not limited to, the cMPOA (Fig.…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…Nts has subsequently been identified throughout the brain (Beck et al, 1989; Carraway and Leeman, 1976; Jennes et al, 1982; Kitabgi et al, 1990; Uhl et al, 1979) and has been implicated in regulating a diverse repertoire of physiology and motivated behaviors including feeding, locomotor activity, social behavior, analgesia, sleep, and response to addictive drugs (Boules et al, 2011; Brown et al, 2017; Cape et al, 2000; Demeule et al, 2014; Ferraro et al, 2016; Fitzpatrick et al, 2012; Gammie et al, 2009; Merullo et al, 2015b; Smith et al, 2012). Nts may direct certain behaviors via actions in the ventral tegmental area (VTA), based on findings that different types of VTA neurons orchestrate distinct goal-directed behaviors (Lammel et al, 2012; Stamatakis et al, 2013; van Zessen et al, 2012), and that a specific subset of VTA neurons expresses neurotensin receptor-1 (Woodworth et al, 2017a).…”

Song in an Affiliative Context Relates to the Neural Expression of Dopamine- and Neurotensin-Related Genes in Male European Starlings

“…Neurotensin (NT) is a candidate neuropeptide to modulate undirected song because it strongly interacts with dopaminergic signaling [Binder et al, 2001] and is implicated in social behavior [Driessen et al, 2014; Gammie et al, 2009; Merullo et al, 2015b; Merullo et al, 2015a] and learning [Azmi et al, 2006; Feifel et al, 2009; Keiser et al, 2014; Laszlo et al, 2010; Tirado-Santiago et al, 2006; Xiao et al, 2014]. NT and the NT1 receptor (NTR1; the only known avian NT receptor [Numao et al, 2011]) co-localize with DA neurons in the ventral tegmental area (VTA) and are also found in LS and Area X [Atoji et al, 1996; Binder et al, 2001; Merullo et al, 2015b; Merullo et al, 2015a; Xie et al, 2010].…”