Browsing by Subject "Fear conditioning"

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    Juvenile stress facilitates safety learning in male and female high alcohol preferring mice
    (Elsevier, 2021) Müller, Iris; Adams, Demitra D.; Sangha, Susan; Chester, Julia A.; Psychology, School of Science
    Adversities during juvenility increase the risk for stress-related disorders, such as post-traumatic stress disorder (PTSD) and alcohol use disorder. However, stress can also induce coping mechanisms beneficial for later stressful experiences. We reported previously that mice selectively bred for high alcohol preference (HAP) exposed to stress during adolescence (but not during adulthood) showed enhanced fear-conditioned responses in adulthood, as measured by fear-potentiated startle (FPS). However, HAP mice also showed enhanced responding to safety cues predicting the absence of foot shocks in adulthood. Here, we pursue these findings in HAP mice by investigating in further detail how juvenile stress impacts the acquisition of safety and fear learning. HAP mice were subjected to three days of juvenile stress (postnatal days 25, 27, 28) and discriminative safety/fear conditioning in adulthood. FPS was used to assess safety versus fear cue discrimination, fear learning, and fear inhibition by the safety cue. Both stressed and unstressed HAP mice were able to discriminate between both cues as well as learn the fear cue-shock association. Interestingly, it was only the previously stressed mice that were able to inhibit their fear response when the fear cue was co-presented with the safety cue, thus demonstrating safety learning. We also report an incidental finding of alopecia in the juvenile stress groups, a phenotype seen in stress-related disorders. These results in HAP mice may be relevant to understanding the influence of juvenile trauma for individual risk and resilience toward developing PTSD and how individuals might benefit from safety cues in behavioral psychotherapy.
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    Orexin Depolarizes Central Amygdala Neurons via Orexin Receptor 1, Phospholipase C and Sodium-Calcium Exchanger and Modulates Conditioned Fear
    (Frontiers, 2018-12-18) Dustrude, Erik T.; Caliman, Izabela F.; Bernabe, Cristian S.; Fitz, Stephanie D.; Grafe, Laura A.; Bhatnagar, Seema; Bonaventure, Pascal; Johnson, Philip L.; Molosh, Andrei I.; Shekhar, Anantha; Psychiatry, School of Medicine
    Orexins (OX), also known as hypocretins, are excitatory neuropeptides with well-described roles in regulation of wakefulness, arousal, energy homeostasis, and anxiety. An additional and recently recognized role of OX is modulation of fear responses. We studied the OX neurons of the perifornical hypothalamus (PeF) which send projections to the amygdala, a region critical in fear learning and fear expression. Within the amygdala, the highest density of OX-positive fibers was detected in the central nucleus (CeA). The specific mechanisms underlying OX neurotransmission within the CeA were explored utilizing rat brain slice electrophysiology, pharmacology, and chemogenetic stimulation. We show that OX induces postsynaptic depolarization of medial CeA neurons that is mediated by OX receptor 1 (OXR1) but not OX receptor 2 (OXR2). We further characterized the mechanism of CeA depolarization by OX as phospholipase C (PLC)- and sodium-calcium exchanger (NCX)- dependent. Selective chemogenetic stimulation of OX PeF fibers recapitulated OXR1 dependent depolarization of CeA neurons. We also observed that OXR1 activity modified presynaptic release of glutamate within the CeA. Finally, either systemic or intra-CeA perfusion of OXR1 antagonist reduced the expression of conditioned fear. Together, these data suggest the PeF-CeA orexinergic pathway can modulate conditioned fear through a signal transduction mechanism involving PLC and NCX activity and that selective OXR1 antagonism may be a putative treatment for fear-related disorders.