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Browsing by Author "Lowry, Christopher A."
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Item Crh receptor priming in the bed nucleus of the stria terminalis induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety(Elsevier, 2020-01-10) Donner, Nina C.; Mani, Sofia; Fitz, Stephanie D.; Kienzle, Drake M.; Shekhar, Anantha; Lowry, Christopher A.; Psychiatry, School of MedicineThe bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear. Since the BNST projects heavily to the dorsal raphe nucleus (DR), the main source of brain serotonin, we here tested the hypothesis that such repeated, anxiety-inducing activation of Crh receptors in the BNST alters the expression of serotonergic genes in the DR, including tph2, the gene encoding the rate-limiting enzyme for brain serotonin synthesis, and slc6a4, the gene encoding the serotonin transporter (SERT). For 5 days, adult male Wistar rats received daily, bilateral, intra-BNST microinjections of vehicle (1% bovine serum albumin in 0.9% saline, n = 11) or behaviorally subthreshold doses of urocortin 1 (Ucn1, n = 11), a potent Crh receptor agonist. Priming with Ucn1 increased tph2 mRNA expression selectively within the anxiety-related dorsal part of the DR (DRD) and decreased social interaction (SI) time, a measure of anxiety-related defensive behavioral responses in rodents. Decreased social interaction was strongly correlated with increased tph2 mRNA expression in the DRD. Together with previous studies, our data are consistent with the hypothesis that Crh-mediated control of the BNST/DRD-serotonergic system plays a key role in the development of chronic anxiety states, possibly also contributing to stress-induced relapses in drug abuse and addiction behavior.Item Differential effects of exposure to low-light or high-light open-field on anxiety-related behaviors: Relationship to c-Fos expression in serotonergic and non-serotonergic neurons in the dorsal raphe nucleus(Elsevier, 2007-04-02) Bouwknecht, J. Adriaan; Spiga, Francesca; Staub, Daniel R.; Hale, Matthew W.; Shekhar, Anantha; Lowry, Christopher A.; Psychiatry, School of MedicineSerotonergic systems arising from the mid-rostrocaudal and caudal dorsal raphe nucleus (DR) have been implicated in the facilitation of anxiety-related behavioral responses to anxiogenic drugs or aversive stimuli. In this study we attempted to determine a threshold to engage serotonergic neurons in the DR following exposure to aversive conditions in an anxiety-related behavioral test. We manipulated the intensity of anxiogenic stimuli in studies of male Wistar rats by leaving them undisturbed (CO), briefly handling them (HA), or exposing them to an open-field arena for 15-min under low-light (LL: 8–13 lx) or high-light (HL: 400–500 lx) conditions. Rats exposed to HL conditions responded with reduced locomotor activity, reduced time spent exploring the center of the arena, a lower frequency of rearing and grooming, and an increased frequency of facing the corner of the arena compared to LL rats. Rats exposed to HL conditions had small but significant increases in c-Fos expression within serotonergic neurons in subdivisions of the rostral DR. Exposure to HL conditions did not alter c-Fos responses in serotonergic neurons in any other DR subdivision. In contrast, rats exposed to the open-field arena had increased c-Fos expression in non-serotonergic cells throughout the DR compared to CO rats, and this effect was particularly apparent in the dorsolateral part of the DR. We conclude that exposure to HL conditions, compared to LL conditions, increased anxiety-related behavioral responses in an open-field arena but this stimulus was at or below the threshold required to increase c-Fos expression in serotonergic neurons.Item Elevated tph2 mRNA expression in a rat model of chronic anxiety(Wiley, 2012-04) Donner, Nina C.; Johnson, Philip L.; Fitz, Stephanie D.; Kellen, Karen E.; Shekhar, Anantha; Lowry, Christopher A.; Psychiatry, School of MedicineBACKGROUND: Allelic variations in TPH2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-HT) biosynthesis, may be genetic predictors of panic disorder and panic responses to panicogenic challenges in healthy volunteers. To test the hypothesis that tph2 mRNA is altered in chronic anxiety states, we measured tph2 expression in an established rat model of panic disorder. METHODS: We implanted 16 adult, male rats with bilateral guide cannulae and then primed them with daily injections of the corticotropin-releasing factor (CRF) receptor agonist, urocortin 1 (UCN1, 6 fmoles/100 nl per side, n = 8) or vehicle (n = 8) into the basolateral amygdaloid complex (BL) for 5 consecutive days. Anxiety-like behavior was assessed, 24 hr prior to and 48 hr following priming, in the social interaction (SI) test. A third group (n = 7) served as undisturbed home cage controls. All rats were killed 3 days after the last intra-BL injection to analyze tph2 and slc6a4 (gene encoding the serotonin transporter, SERT) mRNA expression in the dorsal raphe nucleus (DR), the main source of serotonergic projections to anxiety-related brain regions, using in situ hybridization histochemistry. RESULTS: UCN1 priming increased anxiety-related behavior in the SI test compared to vehicle-injected controls and elevated tph2, but not slc6a4, mRNA expression in DR subregions, including the ventrolateral DR/ventrolateral periaqueductal gray (DRVL/VLPAG), a subregion previously implicated in control of panic-related physiologic responses. Tph2 mRNA expression in the DRVL/VLPAG was correlated with increased anxiety-related behavior. CONCLUSION: Our data support the hypothesis that chronic anxiety states are associated with dysregulated tph2 expression.Item 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 MedicineThe 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.Item Using loss- and gain-of-function approaches to target amygdala-projecting serotonergic neurons in the dorsal raphe nucleus that enhance anxiety-related and conditioned fear behaviors(Sage, 2020) Bernabe, Cristian S.; Caliman, Izabela F.; Truitt, William A.; Molosh, Andrei I.; Lowry, Christopher A.; Hay-Schmidt, Anders; Shekhar, Anantha; Johnson, Philip L.; Anatomy, Cell Biology and Physiology, School of MedicineBackground: The central serotonergic system originating from the dorsal raphe nucleus (DR) plays a critical role in anxiety and trauma-related disorders such as posttraumatic stress disorder. Although many studies have investigated the role of serotonin (5-HT) within pro-fear brain regions such as the amygdala, the majority of these studies have utilized non-selective pharmacological approaches or poorly understood lesioning techniques which limit their interpretation. Aim: Here we investigated the role of amygdala-projecting 5-HT neurons in the DR in innate anxiety and conditioned fear behaviors. Methods: To achieve this goal, we utilized (1) selective lesion of 5-HT neurons projecting to the amygdala with saporin toxin conjugated to anti-serotonin transporter (SERT) injected into the amygdala, and (2) optogenetic excitation of amygdala-projecting DR cell bodies with a combination of a retrogradely transported canine adenovirus-expressing Cre-recombinase injected into the amygdala and a Cre-dependent-channelrhodopsin injected into the DR. Results: While saporin treatment lesioned both local amygdalar 5-HT fibers and neurons in the DR as well as reduced conditioned fear behavior, optical activation of amygdala-projecting DR neurons enhanced anxious behavior and conditioned fear response. Conclusion: Collectively, these studies support the hypothesis that amygdala-projecting 5-HT neurons in the DR represent an anxiety and fear-on network.