Contents lists available at ScienceDirect Neurobiology of Learning and Memory journal homepage: www.elsevier.com/locate/ynlme Basolateral amygdala Thy1-expressing neurons facilitate the inhibition of contextual fear during consolidation, reconsolidation, and extinction T. Lee Gilman 1 , Sohini Dutta, Jordan M. Adkins, Cassandra A. Cecil, Aaron M. Jasnow ⁎ Department of Psychological Sciences and Brain Health Research Institute, 144 Kent Hall, Kent State University, Kent, OH 44242, USA ARTICLE INFO Keywords: Basolateral amygdala Thy1-expressing neurons DREADDs Contextual fear Inhibitory avoidance ABSTRACT Disrupted fear inhibition is a characteristic of many anxiety disorders. Investigations into the neural mechanisms responsible for inhibiting fear will improve understanding of the essential circuits involved, and facilitate de- velopment of treatments that promote their activity. Within the basolateral amygdala (BLA), Thy1-expressing neuron activity has been characterized by us and others as promoting fear inhibition to discrete fear cues by influencing consolidation of cued fear learning or cued fear extinction. Here, we evaluated how activating BLA Thy1-expressing neurons using DREADDs affected the consolidation, expression, reconsolidation, and extinction of contextual fear. Using an inhibitory avoidance paradigm, our present findings indicate a similar involvement of BLA Thy1-expressing neuron activity in the consolidation and extinction, but not expression, of fear. Importantly, our data also provide the first evidence for involvement of these neurons in inhibiting fear re- consolidation. Therefore, these data enhance our understanding of the roles that Thy1-expressing neurons within the BLA play in inhibiting fear when examining avoidance, in addition to the already established role in Pavlovian fear paradigms. Future investigations should further explore the circuits responsible for these con- textual effects modulated by BLA Thy1 neuron activation, and could promulgate development of therapies targeting these neurons and their downstream effectors. 1. Introduction As essential as fear is to an organism’s survival, so too is an or- ganism’s ability to inhibit fear. Insufficient inhibition of fear can impair the execution of behaviors supporting survival in animals (e.g., fora- ging, reproduction), as well as interrupt daily human activities in- cluding eating, working, and socializing. Indeed, an inability to inhibit fearful responses to stimuli in humans can result in neuropsychiatric disorders such as specific phobias or more generalized fear disorders, including post-traumatic stress disorder, social anxiety disorder, and generalized anxiety disorder (Christianson et al., 2012; Graham & Milad, 2011; Grupe & Nitschke, 2013; Lopresto, Schipper, & Homberg, 2016; Quirk & Gehlert, 2003). Understanding how the brain can inhibit fear will not only advance comprehension of the complex circuits re- sponsible for emotion regulation, but also facilitate identification of novel pathways and mechanisms integral to the development of more efficacious therapeutic strategies. One of the subnuclei within the amygdala, the basolateral amygdala (BLA), is central to a fear circuit that regulates responses to discrete as well as ambiguous fear cues (Davis, 1997; Rosen & Schulkin, 1998). Indeed, the BLA possesses a critical role in the regulation of fear and anxiety behaviors (see Tovote, Fadok, & Luthi, 2015). We previously hypothesized that a cell population in the BLA identified by Lüthi and colleagues as “extinction neurons” (Herry et al., 2008), neurons that become more active during extinction learning, might overlap with glutamatergic Thy1-expressing neurons. In agreement with this hy- pothesis, we found that fear inhibition to auditory fear cues was fa- cilitated by optogenetic activation of Thy1-expressing neurons (Jasnow et al., 2013). This was the first characterization of the behavioral effects of activating Thy1 neurons, as most researchers primarily employ mice with Thy1 promoter-driven transgenes as reporter lines to drive ex- pression in a fraction of forebrain glutamatergic projection neurons (Dana et al., 2014; Feng et al., 2000; Heldt et al., 2014; Oakley et al., 2006; Porrero, Rubio-Garrido, Avendaño, & Clascá, 2010; Zagoraiou et al., 2009). Further supporting a fear-inhibiting role of Thy1 neurons in the https://doi.org/10.1016/j.nlm.2018.09.010 Received 13 April 2018; Received in revised form 15 August 2018; Accepted 26 September 2018 ⁎ Corresponding author at: Department of Psychological Sciences and Brain Health Research Institute, Kent State University, 230 Kent Hall, Kent, OH 44242, USA. 1 Present address: Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-7756, USA. E-mail addresses: tgilman@kent.edu (T.L. Gilman), sdutta1@kent.edu (S. Dutta), jadkin26@kent.edu (J.M. Adkins), cassc@umich.edu (C.A. Cecil), ajasnow@kent.edu (A.M. Jasnow). Neurobiology of Learning and Memory 155 (2018) 498–507 Available online 01 October 2018 1074-7427/ © 2018 Elsevier Inc. All rights reserved. T