McIntyre-Rodriguez, Christa

Permanent URI for this collectionhttps://hdl.handle.net/10735.1/2875

Dr. McIntyre-Rodriguez's research is aimed at gaining information regarding the neuronal signals that determine whether a memory will be stored for the long term and may shed some light on the precise mechanisms involved in the synaptic changes that underlie memory. Such knowledge may ultimately be used to benefit individuals suffering from various memory disorders including Alzheimer's disease and post traumatic stress disorder.

Learn more about Christa McIntyre-Rodriguez on her BBS People and Research Explorer pages.

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Recent Submissions

Now showing 1 - 10 of 10
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    Vagus Nerve Stimulation as a Tool for Enhancing Extinction in Exposure-Based Therapies
    (Springer, 2019-01) Noble, Lindsey J.; Souza, Rimenez R.; McIntyre, Christa K.; 0000-0002-8138-5023 (McIntyre, CK); Noble, Lindsey J.; Souza, Rimenez R.; McIntyre, Christa K.
    Rationale Emotionally traumatic experiences can lead to maladaptive memories that are enduring and intrusive. The goal of exposure-based therapies is to extinguish conditioned fears through repeated, unreinforced exposures to reminders of traumatic events. The extinction of conditioned fear depends upon the consolidation of new memories made during exposure to reminders. An impairment in extinction recall, observed in certain patient populations, can interfere with progress in exposure-based therapies, and the drive to avoid thoughts and reminders of the trauma can undermine compliance and increase dropout rate. Effective adjuncts to exposure-based therapies should improve the consolidation and maintenance of the extinction memory or improve the tolerability of the therapy. Under stressful conditions, the vagus nerve responds to elevations in epinephrine and signals the brain to facilitate the storage of new memories while, as part of the parasympathetic nervous system, it slows the sympathetic response. Objective Here, we review studies relevant to fear extinction, describing the anatomical and functional characteristics of the vagus nerve and mechanisms of vagus nerve stimulation (VNS)-induced memory enhancement and plasticity. Results We propose that stimulation of the left cervical vagus nerve during exposure to conditioned cues signals the brain to store new memories just as epinephrine or emotional arousal would do, but bypasses the peripheral sympathetic fight-or-flight response. Conclusions In support of this hypothesis, we have found that VNS accelerates extinction and prevents reinstatement of conditioned fear in rats. Finally, we propose future studies targeting the optimization of stimulation parameters and the search for biomarkers of VNS effectiveness that may improve exposure therapy outcomes.
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    Vagus Nerve Stimulation Promotes Generalization of Conditioned Fear Extinction and Reduces Anxiety in Rats
    (Elsevier Science Inc, 2018-09-21) Noble, Lindsey J.; Meruva, Venkat B.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Christa K.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Noble, Lindsey J.; Meruva, Venkat B.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Christa K.
    Background: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.
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    Vagus Nerve Stimulation Reverses the Extinction Impairments in a Model of PTSD with Prolonged and Repeated Trauma
    (Taylor and Francis Ltd, 2019-04-23) Souza, Rimenez R.; Robertson, Nicole M.; Pruitt, David T.; Gonzales, Phillip A.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Crista K.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Souza, Rimenez R.; Robertson, Nicole M.; Pruitt, David T.; Gonzales, Phillip A.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Crista K.
    We have shown that vagus nerve stimulation (VNS) enhances extinction of conditioned fear and reduces anxiety in rat models of PTSD using moderate stress. However, it is still unclear if VNS can be effective in enhancing extinction of severe fear after prolonged and repeated trauma. Severe fear was induced in adult male rats by combining single prolonged stress (SPS) and protracted aversive conditioning (PAC). After SPS and PAC procedures, rats were implanted with stimulating cuff electrodes, exposed to five days of extinction training with or without VNS, and then tested for extinction retention, return of fear in a new context and reinstatement. The elevated plus maze, open field and startle were used to test anxiety. Sham rats showed no reduction of fear during extensive extinction training. VNS-paired with extinction training reduced freezing at the last extinction session by 70% compared to sham rats. VNS rats exhibited half as much fear as shams, as well as less fear renewal. Sham rats exhibited significantly more anxiety than naive controls, whereas VNS rats did not. These results demonstrate that VNS enhances extinction and reduces anxiety in a severe model of PTSD that combined SPS and a conditioning procedure that is 30 times more intense than the conditioning procedures in previous VNS studies. The broad utility of VNS in enhancing extinction learning in rats and the strong clinical safety record of VNS suggest that VNS holds promise as an adjuvant to exposure-based therapy in people with PTSD and other complex forms of this condition. ©2019 Informa UK Limited, trading as Taylor & Francis Group.
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    Basolateral Amygdala Inputs to the Medial Entorhinal Cortex Selectively Modulate the Consolidation of Spatial and Contextual Learning
    (Soc Neuroscience) Wahlstrom, Krista L.; Huff, Mary L.; Emmons, Eric B.; Freeman, John H.; Narayanan, Nandakumar S.; McIntyre, Christa K.; LaLumiere, Ryan T.; McIntyre, Christa K.
    Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning. To address several questions regarding this issue, male Sprague Dawley rats received optogenetic manipulations of different BLA afferents immediately after training in different learning tasks. Optogenetic stimulation of the BLA-mEC pathway using ChR2(E123A) after spatial and cued-response Barnes maze training enhanced and impaired retention, respectively, whereas optical inhibition of the pathway using eNpHR3.0 produced trends in the opposite direction. Similar stimulation of the BLA-posterior dorsal striatum pathway had no effect. BLA-mEC stimulation also selectively enhanced retention for the contextual, but not foot shock, component of a modified contextual fear-conditioning procedure. In both sets of experiments, only stimulation using bursts of 8 Hz light pulses significantly enhanced retention, suggesting the importance of driving activity in this frequency range. An 8 Hz stimulation of the BLA- mEC pathway increased local field potential power in the same frequency range in the mEC and in the DH. Together, the present findings suggest that the BLA modulates the consolidation of spatial/contextual memory via projections to the mEC and that activity within the 8 Hz range is critical for this modulation.
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    Basolateral Amygdala Inputs to the Medial Entorhinal Cortex Selectively Modulate the Consolidation of Spatial and Contextual Learning
    (Soc Neuroscience) Wahlstrom, Krista L.; Huff, Mary L.; Emmons, Eric B.; Freeman, John H.; Narayanan, Nandakumar S.; McIntyre, Christa K.; LaLumiere, Ryan T.; McIntyre, Christa K.
    Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning. To address several questions regarding this issue, male Sprague Dawley rats received optogenetic manipulations of different BLA afferents immediately after training in different learning tasks. Optogenetic stimulation of the BLA-mEC pathway using ChR2(E123A) after spatial and cued-response Barnes maze training enhanced and impaired retention, respectively, whereas optical inhibition of the pathway using eNpHR3.0 produced trends in the opposite direction. Similar stimulation of the BLA-posterior dorsal striatum pathway had no effect. BLA-mEC stimulation also selectively enhanced retention for the contextual, but not foot shock, component of a modified contextual fear-conditioning procedure. In both sets of experiments, only stimulation using bursts of 8 Hz light pulses significantly enhanced retention, suggesting the importance of driving activity in this frequency range. An 8 Hz stimulation of the BLA- mEC pathway increased local field potential power in the same frequency range in the mEC and in the DH. Together, the present findings suggest that the BLA modulates the consolidation of spatial/contextual memory via projections to the mEC and that activity within the 8 Hz range is critical for this modulation.
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    Using the Single Prolonged Stress Model to Examine the Pathophysiology of PTSD
    (Frontiers Media SA) Souza, Rimenez R.; Noble, Lindsey J.; McIntyre, Christa K.; Souza, Rimenez R.; Noble, Lindsey J.; McIntyre, Christa K.
    The endurance of memories of emotionally arousing events serves the adaptive role of minimizing future exposure to danger and reinforcing rewarding behaviors. However, following a traumatic event, a subset of individuals suffers from persistent pathological symptoms such as those seen in posttraumatic stress disorder (PTSD). Despite the availability of pharmacological treatments and evidence-based cognitive behavioral therapy, a considerable number of PTSD patients do not respond to the treatment, or show partial remission and relapse of the symptoms. In controlled laboratory studies, PTSD patients show deficient ability to extinguish conditioned fear. Failure to extinguish learned fear could be responsible for the persistence of PTSD symptoms such as elevated anxiety, arousal, and avoidance. It may also explain the high non-response and dropout rates seen during treatment. Animal models are useful for understanding the pathophysiology of the disorder and the development of new treatments. This review examines studies in a rodent model of PTSD with the goal of identifying behavioral and physiological factors that predispose individuals to PTSD symptoms. Single prolonged stress (SPS) is a frequently used rat model of PTSD that involves exposure to several successive stressors. SPS rats show PTSD-like symptoms, including impaired extinction of conditioned fear. Since its development by the Liberzon lab in 1997, the SPS model has been referred to by more than 200 published papers. Here we consider the findings of these studies and unresolved questions that may be investigated using the model.
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    Effects of Vagus Nerve Stimulation on Extinction of Conditioned Fear and Post-Traumatic Stress Disorder Symptoms in Rats
    Noble, Lindsey J.; Gonzalez, I. J.; Meruva, V. B.; Callahan, Kathleen A.; Belfort, Benjamin D.; Ramanathan, K. R.; Meyers, Eric; Kilgard, Michael P.; Rennaker, Robert L.; McIntyre, Christa K.; Noble, Lindsey J.; Gonzalez, I. J.; Meruva, V. B.; Callahan, Kathleen A.; Belfort, Benjamin D.; Ramanathan, K. R.; Meyers, Eric; Kilgard, Michael P.; Rennaker, Robert L.; McIntyre, Christa K.
    Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.
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    Impaired Spatial Memory and Enhanced Habit Memory in a Rat Model of Post-Traumatic Stress Disorder
    (Frontiers Media SA) Goodman, Jarid; McIntyre, Christa K.; Goodman, Jarid; McIntyre, Christa K.
    High levels of emotional arousal can impair spatial memory mediated by the hippocampus, and enhance stimulus-response (S-R) habit memory mediated by the dorsolateral striatum (DLS). The present study was conducted to determine whether these memory systems may be similarly affected in an animal model of post-traumatic stress disorder (PTSD). Sprague-Dawley rats were subjected to a "single-prolonged stress" (SPS) procedure and 1 week later received training in one of two distinct versions of the plus-maze: a hippocampus-dependent place learning task or a DLS-dependent response learning task. Results indicated that, relative to non-stressed control rats, SPS rats displayed slower acquisition in the place learning task and faster acquisition in the response learning task. In addition, extinction of place learning and response learning was impaired in rats exposed to SPS, relative to non-stressed controls. The influence of SPS on hippocampal spatial memory and DLS habit memory observed in the present study may be relevant to understanding some common features of PTSD, including hippocampal memory deficits, habit-like avoidance responses to trauma-related stimuli, and greater likelihood of developing drug addiction and alcoholism.
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    Emotional Modulation of Synapses, Circuits and Memory
    (Frontiers Research Foundation) Ploski, Jonathan E.; McIntyre, Christa K.
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    Memory-Enhancing Intra-Basolateral Amygdala Infusions of Clenbuterol Increase Arc and Camkiiα Protein Expression in the Rostral Anterior Cingulate Cortex
    Holloway-Erickson, Crystal M.; McReynolds, Jayme R.; McIntyre, Christa K.
    Activation of β-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory through interactions with multiple memory systems. The cellular mechanisms for this interaction remain unresolved. Memory-modulating BLA manipulations influence expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc) in the dorsal hippocampus, and hippocampal expression of Arc protein is critically involved in memory consolidation and long-term potentiation. The present studies examined whether this influence of the BLA is specific to the hippocampus and to Arc protein. Like the hippocampus, the rostral portion of the anterior cingulate cortex (rACC) is involved in the consolidation of inhibitory avoidance (IA) memory, and IA training increases Arc protein in the rACC. Because the BLA interacts with the rACC in the consolidation of IA memory, the rACC is a potential candidate for further studies of BLA modulation of synaptic plasticity. The alpha isoform of the Calcium/Calmodulin-dependent protein kinase II (CaMKIIα) and the immediate early gene c-Fos are involved in long-term potentiation and memory. Both Arc and CaMKIIα proteins can be translated in isolated synapses, where the mRNA is localized, but c-Fos protein remains in the soma. To examine the influence of memory-modulating manipulations of the BLA on expression of these memory and plasticity-associated proteins in the rACC, male Sprague-Dawley rats were trained on an IA task and given intra-BLA infusions of either clenbuterol or lidocaine immediately after training. Findings suggest that noradrenergic stimulation of the BLA may modulate memory consolidation through effects on both synaptic proteins Arc and CaMKIIα, but not the somatic protein c-Fos. Furthermore, protein changes observed in the rACC following BLA manipulations suggest that the influence of the BLA on synaptic proteins is not limited to those in the dorsal hippocampus.

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