Astrocyte Modulation of Fear Learning

Neuro-glial signaling pathways are known to influence complex behavior, including fear learning processes that may contribute to the development of psychopathological conditions like Post-Traumatic Stress Disorder (PTSD). Recent findings from our laboratory have demonstrated a contribution of proinflammatory cytokine expression in the dorsal hippocampus to such fear learning processes. Astrocytes are thought to be the primary cellular source of this expression, but technological limitations have thus far prevented researchers from selectively isolating the precise contribution of astrocytes to this expression. We utilized Designer Receptors Exclusively Activated by Design Drugs (DREADDs) to examine the role of astrocyte signaling in the dorsal hippocampus in fear learning. We expressed a Gq-coupled DREADD virus under an astrocyte specific promoter such we could test whether activating Gq signaling in astrocytes prior to fear conditioning influenced contextual fear learning. We found that activating Gq-signaling in hippocampal astrocytes enhanced contextual fear learning. This finding suggests that gliotransmission driven by astrocytes in the dorsal hippocampus directly enhances fear learning and supports the feasibility of employing glial-expressing DREADD technology to examine astrocyte function in complex behavior.Bachelor of Scienc

The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning

Posttraumatic stress disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we used stress-enhanced fear learning (SEFL), an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus (DH). There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, intracerebroventricular (i.c.v.), 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the DH induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL and suggest that IL-1 signaling in the brain may have a critical role in the development of PTSD

Inverted Pendulum Exhibit for the Ann Arbor Hands-On Museum

ME450 Capstone Design and Manufacturing Experience: Winter 2010This project involves designing and building a mechatronics exhibit for the Ann Arbor Hands-On museum. The exhibit consists of an inverted pendulum system that utilizes feedback controls in order to balance a free pendulum in its inverted state. The exhibit will be made up of a manual pendulum system, in which patrons will attempt to balance the pendulum on their own, and automatic pendulum system that will use a microprocessor and feedback controls to balance the pendulum. The purpose of the exhibit is for the patrons of the museum to gain an understanding of how a mechatronics system and feedback controls work.http://deepblue.lib.umich.edu/bitstream/2027.42/109384/1/me450w10project2_report.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/109384/2/me450w10project2_photo.jp

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"References" at end of most of the chapters.Mode of access: Internet

Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana”) in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance

Axially Chiral Cannabinoids: Design, Synthesis, and Cannabinoid Receptor Affinity

The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics target-ing the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an addi-tional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This “es-cape from flatland” is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ush-ering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug develop-ment. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atro-pisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain—and in some cases, strengthen—affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex en-docannabinoid system