113 113 Internal State-Dependent Conditioned Stimulus Internal State-Dependent Conditioned Stimulus Delivery using Cardiovascular Telemetry in Mice Delivery using Cardiovascular Telemetry in Mice BENJAMIN TURLEY BENJAMIN TURLEY 1 1 , ADAM SWIERCZ , ADAM SWIERCZ 2 2 , LAXMI IYER , LAXMI IYER 2 2 , PAUL MARVAR , PAUL MARVAR 2-3 2-3 ABSTRACT ABSTRACT • • To further understand mechanisms of neuropsychiatric disease(s) and their impact on physiological systems, improved pre-clinical models and innovative methodology are needed to assess the internal physiological state of the animal in real-time. To address this challenge we developed a customizable software-based program for Ponemah™ that takes into account the animal’s diurnal and resting cardiovascular state in a home-cage environment. Using an integrated Pavlovian fear conditioning and cardiovascular telemetry approach in mice, we demonstrate for the frst time a novel software application that can remotely trigger a conditioned stimulus (CS) (i.e., audible tone) based on the animal’s instantaneous cardiovascular state while in its home-cage environment. This new cardiovascular behavioral tool using cardiovascular telemetry extends the ability to quantify integrated physiological correlates of learned fear and may aid in further understanding mechanisms related to enhanced cardiovascular and autonomic arousal in fear and anxiety- based disorders. INTRODUCTION INTRODUCTION As demand grows for more sophisticated approaches to quantify and analyze integrated multi-modal and internal state-dependent rodent behaviors, new approaches for detection and quantifcation are needed. Wireless telemetry in freely moving rodents is commonly used to quantify and monitor cardiovascular autonomic responses. This approach allows for in vivo monitoring of blood pressure, heart rate, electroencephalography, and nerve activity in conscious rodents. Integrating wireless telemetry approaches with animal behavioral measures (e.g., Pavlovian fear conditioning) provides a unique way to test the impact of pharmacological, behavioral (e.g., exposure therapy/extinction learning), or other non-invasive interventions (e.g., Transcranial Magnetic Stimulation) on cardiovascular autonomic responses to learned threats and emotional regulation. Using a rodent model, our laboratory has begun to evaluate integrated cardioautonomic and behavioral measures (Swiercz et al., 2020); building upon the pioneering work of Joseph Ledoux, Oliver Stiedl, and others, (Burhans et al., 2010; Iwata & LeDoux, 1988; LeDoux et al., 1988; Schreurs et al., 2005; Stiedl et al., 2009; Stiedl & Spiess, 1997) demonstrating that heart rate, (Tovote et al., 2005) heart rate (HR) variability, (Stiedl et al., 2009) and blood pressure (Hsu et al., 2012) are reliable indicators of fear memory acquisition that can be used to distinguish between nonspecifc and associative threat responses. For example, using an adapted conditioned cardiovascular testing paradigm, we recently showed that recall of a consolidated extinction memory reduces the conditioned cardiovascular response, which is infuenced by context- dependent differences in blood pressure and HR sensitivity (Swiercz et al., 2018). Subsequent studies from our laboratory used the same conditioned cardiovascular testing paradigm to evaluate the role of an angiotensin receptor blocker, losartan, on conditioned cardiovascular threat responses independent of extinction learning (Swiercz et al., 2020). These studies provide an example of how using other physiological measures of inhibitory learning (conditioned cardiovascular responses) may help with quantifying the effcacy of extinction- based interventions and their physiological effects. While associated fear-based cardiovascular responses have been shown to be important physiological correlates of the expression of learned fear and threat responses (Gaburro et al., 2011), there is a signifcant amount of experimental variance implicit in current animal models. Retrieval of the fear conditioned response is often confounded by extraneous environmental factors, which may affect physiological state such as proximity to other animals, foreign scents, noise, or by unrelated 1 NEUROSCIENCE & PSYCHOLOGY, CCAS ‘21 2 GWU DEPARTMENT OF PHARMACOLOGY AND PHYSIOLOGY 3 GWU DEPARTMENT OF PSYCHIATRY AND BEHAVIORAL SCIENCES, pmarvar@gwu.edu KEYWORDS: KEYWORDS: cardiovascular, fear conditioning, telemetry, biofeedback DOI: DOI: https://doi.org/10.4079/2578-9201.4(2021).05