Browsing by Author "Bernabe, Cristian"

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    Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels
    (Springer Nature, 2019-01-22) Johnson, Philip L.; Molosh, Andrei I.; Federici, Lauren M.; Bernabe, Cristian; Haggerty, David; Fitz, Stephanie D.; Nalivaiko, Eugene; Truitt, William; Shekhar, Anantha; Anatomy and Cell Biology, IU School of Medicine
    Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT-/-) have increased baseline anxiety behaviors, SERT+/- rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/- model. Here we sought to determine if SERT+/- or SERT-/-, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT-/- rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/- (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/- rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT-/- and SERT+/- rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.
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    Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning
    (Elsevier, 2015-11) Johnson, Philip L.; Molosh, Andrei; Fitz, Stephanie D.; Arendt, Dave; Deehan, Gerald A.; Federici, Lauren M.; Bernabe, Cristian; Engleman, Eric A.; Rodd, Zachary A.; Lowry, Christopher A.; Shekhar, Anantha; Department of Anatomy and Cell Biology, School of Medicine
    The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC.
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    Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase
    (Nature Publishing Group, 2014-11) Molosh, Andrei I.; Johnson, Philip L.; Spence, John P.; Arendt, David; Federici, Lauren M.; Bernabe, Cristian; Janasik, Steven P.; Segu, Zaneer M.; Khanna, Rajesh; Goswami, Chirayu; Zhu, Weiguo; Park, Su-Jung; Li, Lang; Mechref, Yehia S.; Clapp, D. Wade; Shekhar, Anantha; Department of Psychiatry, IU School of Medicine
    Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1+/−), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1+/− mice showed aberrant amygdala glutamate/GABA neurotransmission