Identification of a novel perifornical-hypothalamic-area-projecting serotonergic system that inhibits innate panic and conditioned fear responses.

The serotonin (5-HT) system is heavily implicated in the regulation of anxiety and trauma-related disorders such as panic disorder and post-traumatic stress disorder, respectively. However, the neural mechanisms of how serotonergic neurotransmission regulates innate panic and fear brain networks are poorly understood. Our earlier studies have identified that orexin (OX)/glutamate neurons within the perifornical hypothalamic area (PFA) play a critical role in adaptive and pathological panic and fear. While site-specific and electrophysiological studies have shown that intracranial injection and bath application of 5-HT inhibits PFA neurons via 5-HT1a receptors, they largely ignore circuit-specific neurotransmission and its physiological properties that occur in vivo. Here, we investigate the role of raphe nuclei 5-HT inputs into the PFA in panic and fear behaviors. We initially confirmed that photostimulation of glutamatergic neurons in the PFA of rats produces robust cardioexcitation and flight/aversive behaviors resembling panic-like responses. Using the retrograde tracer cholera toxin B, we determined that the PFA receives discrete innervation of serotonergic neurons clustered in the lateral wings of the dorsal (lwDRN) and in the median (MRN) raphe nuclei. Selective lesions of these serotonergic projections with saporin toxin resulted in similar panic-like responses during the suffocation-related CO2 challenge and increased freezing to fear-conditioning paradigm. Conversely, selective stimulation of serotonergic fibers in the PFA attenuated both flight/escape behaviors and cardioexcitation responses elicited by the CO2 challenge and induced conditioned place preference. The data here support the hypothesis that PFA projecting 5-HT neurons in the lwDRN/MRN represents a panic/fear-off circuit and may also play a role in reward behavior.

Prior stress and vasopressin promote corticotropin-releasing factor inhibition of serotonin release in the central nucleus of the amygdala.

Corticotropin-releasing factor (CRF) is essential for coordinating endocrine and neural responses to stress, frequently facilitated by vasopressin (AVP). Previous work has linked CRF hypersecretion, binding site changes, and dysfunctional serotonergic transmission with anxiety and affective disorders, including clinical depression. Crucially, CRF can alter serotonergic activity. In the dorsal raphé nucleus and serotonin (5-HT) terminal regions, CRF effects can be stimulatory or inhibitory, depending on the dose, site, and receptor type activated. Prior stress alters CRF neurotransmission and CRF-mediated behaviors. Lateral, medial, and ventral subdivisions of the central nucleus of the amygdala (CeA) produce CRF and coordinate stress responsiveness. The purpose of these experiments was to determine the effect of intracerebroventricular (icv) administration of CRF and AVP on extracellular 5-HT as an index of 5-HT release in the CeA, using in vivo microdialysis in freely moving rats and high performance liquid chromatography (HPLC) analysis. We also examined the effect of prior stress (1 h restraint, 24 h prior) on CRF- and AVP-mediated release of 5-HT within the CeA. Our results show that icv CRF infusion in unstressed animals had no effect on 5-HT release in the CeA. Conversely, in rats with prior stress, CRF caused a profound dose-dependent decrease in 5-HT release within the CeA. This effect was long-lasting (240 min) and was mimicked by CRF plus AVP infusion without stress. Thus, prior stress and AVP functionally alter CRF-mediated neurotransmission and sensitize CRF-induced inhibition of 5-HT release, suggesting that this is a potential mechanism underlying stress-induced affective reactivity in humans.

Evolution of the Growth Hormone Gene Duplication in Passerine Birds.

Birds of the order Passeriformes represent the most speciose order of land vertebrates. Despite strong scientific interest in this super-radiation, genetic traits unique to passerines are not well characterized. A duplicate copy of growth hormone (GH) is the only gene known to be present in all major lineages of passerines, but not in other birds. GH genes plausibly influence extreme life history traits that passerines exhibit, including the shortest embryo-to-fledging developmental period of any avian order. To unravel the implications of this GH duplication, we investigated the molecular evolution of the ancestral avian GH gene (GH or GH1) and the novel passerine GH paralog (GH2), using 497 gene sequences extracted from 342 genomes. Passerine GH1 and GH2 are reciprocally monophyletic, consistent with a single duplication event from a microchromosome onto a macrochromosome in a common ancestor of extant passerines. Additional chromosomal rearrangements have changed the syntenic and potential regulatory context of these genes. Both passerine GH1 and GH2 display substantially higher rates of nonsynonymous codon change than non-passerine avian GH, suggesting positive selection following duplication. A site involved in signal peptide cleavage is under selection in both paralogs. Other sites under positive selection differ between the two paralogs, but many are clustered in one region of a 3D model of the protein. Both paralogs retain key functional features and are actively but differentially expressed in two major passerine suborders. These phenomena suggest that GH genes may be evolving novel adaptive roles in passerine birds.

Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats.

PURPOSE: Intraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures. METHODS: Sprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI). RESULTS: Administration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8-40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4-16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015). CONCLUSIONS: DORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.

Population structure, intergroup interaction, and human contact govern infectious disease impacts in mountain gorilla populations.

Infectious zoonotic diseases are a threat to wildlife conservation and global health. They are especially a concern for wild apes, which are vulnerable to many human infectious diseases. As ecotourism, deforestation, and great ape field research increase, the threat of human-sourced infections to wild populations becomes more substantial and could result in devastating population declines. The endangered mountain gorillas (Gorilla beringei beringei) of the Virunga Massif in east-central Africa suffer periodic disease outbreaks and are exposed to infections from human-sourced pathogens. It is important to understand the possible risks of disease introduction and spread in this population and how human contact may facilitate disease transmission. Here we present and evaluate an individual-based, stochastic, discrete-time disease transmission model to predict epidemic outcomes and better understand health risks to the Virunga mountain gorilla population. To model disease transmission we have derived estimates for gorilla contact, interaction, and migration rates. The model shows that the social structure of gorilla populations plays a profound role in governing disease impacts with subdivided populations experiencing less than 25% of the outbreak levels of a single homogeneous population. It predicts that gorilla group dispersal and limited group interactions are strong factors in preventing widespread population-level outbreaks of infectious disease after such diseases have been introduced into the population. However, even a moderate amount of human contact increases disease spread and can lead to population-level outbreaks.

Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination.

Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency of YFV-specific memory CD8 T cells and deuterium enrichment in those cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.1% per day, ∼ double the estimated values for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically.

Exploring the functional composition of the human microbiome using a hand-curated microbial trait database.

BACKGROUND: Even when microbial communities vary wildly in their taxonomic composition, their functional composition is often surprisingly stable. This suggests that a functional perspective could provide much deeper insight into the principles governing microbiome assembly. Much work to date analyzing the functional composition of microbial communities, however, relies heavily on inference from genomic features. Unfortunately, output from these methods can be hard to interpret and often suffers from relatively high error rates. RESULTS: We built and analyzed a domain-specific microbial trait database from known microbe-trait pairs recorded in the literature to better understand the functional composition of the human microbiome. Using a combination of phylogentically conscious machine learning tools and a network science approach, we were able to link particular traits to areas of the human body, discover traits that determine the range of body areas a microbe can inhabit, and uncover drivers of metabolic breadth. CONCLUSIONS: Domain-specific trait databases are an effective compromise between noisy methods to infer complex traits from genomic data and exhaustive, expensive attempts at database curation from the literature that do not focus on any one subset of taxa. They provide an accurate account of microbial traits and, by limiting the number of taxa considered, are feasible to build within a reasonable time-frame. We present a database specific for the human microbiome, in the hopes that this will prove useful for research into the functional composition of human-associated microbial communities.

Selection influences naive CD8+ TCR-ß repertoire sharing.

Within each individual, the adaptive immune system generates a repertoire of cells expressing receptors capable of recognizing diverse potential pathogens. The theoretical diversity of the T-cell receptor (TCR) repertoire exceeds the actual size of the T-cell population in an individual by several orders of magnitude - making the observation of identical TCRs in different individuals extremely improbable if all receptors were equally likely. Despite this disparity between the theoretical and the realized diversity of the repertoire, these 'public' receptor sequences have been identified in autoimmune, cancer and pathogen interaction contexts. Biased generation processes explain the presence of public TCRs in the naive repertoire, but do not adequately explain the different abundances of these public TCRs. We investigate and characterize the distribution of genomic TCR-ß sequences of naive CD8+ T cells from three genetically identical mice, comparing non-productive (non-functional sequences) and productive sequences. We find public TCR-ß sequences at higher abundances compared with unshared sequences in the productive, but not in the non-productive, repertoire. We show that neutral processes such as recombination biases, codon degeneracy and generation probability do not fully account for these differences, and conclude that thymic or peripheral selection plays an important role in increasing the abundances of public TCR-ß sequences.

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans.

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

The Rewarding and Anxiolytic Properties of Ethanol within the Central Nucleus of the Amygdala: Mediated by Genetic Background and Nociceptin.

In humans, alcohol is consumed for its rewarding and anxiolytic effects. The central nucleus of the amygdala (CeA) is considered a neuronal nexus that regulates fear, anxiety, and drug self-administration. Manipulations of the CeA alter ethanol (EtOH) consumption under numerous EtOH self-administration models. The experiments determined whether EtOH is reinforcing/anxiolytic within the CeA, whether selective breeding for high alcohol consumption alters the rewarding properties of EtOH in the CeA, and whether the reinforcing/anxiolytic effects of EtOH in the CeA are mediated by the neuropeptides corticotropin-releasing factor (CRF) and nociceptin. The reinforcing properties of EtOH were determined by having male Wistar and Taconic alcohol-preferring (tP) rats self-administer EtOH directly into the CeA. The expression of anxiety-like behaviors was assessed through multiple behavioral models (social interaction, acoustic startle, and open field). Coadministration of EtOH and a CRF1 antagonist (NBI35965) or nociceptin on self-administration into the CeA and anxiety-like behaviors was determined. EtOH was self-administered directly into the lateral CeA, and tP rats self-administered a lower concentration of EtOH than Wistar rats. EtOH microinjected into the lateral CeA reduced the expression of anxiety-like behaviors, indicating an anxiolytic effect. Coadministration of NBI35965 failed to alter the rewarding/anxiolytic properties of EtOH in the CeA. In contrast, coadministration of the nociceptin enhanced both EtOH reward and anxiolysis in the CeA. Overall, the data indicate that the lateral CeA is a key anatomic location that mediates the rewarding and anxiolytic effects of EtOH, and local nociceptin receptors, but not local CRF1 receptors, are involved in these behaviors. SIGNIFICANCE STATEMENT: Alcohol is consumed for the stimulatory, rewarding, and anxiolytic properties of the drug of abuse. The current data are the first to establish that alcohol is reinforcing and anxiolytic within the lateral central nucleus of the amygdala (CeA) and that the nociceptin system regulates these effects of alcohol within the CeA.

Avoidance of Self during CRISPR Immunization.

The battle between microbes and their viruses is ancient and ongoing. Clustered regularly interspaced short palindromic repeat (CRISPR) immunity, the first and, to date, only form of adaptive immunity found in prokaryotes, represents a flexible mechanism to recall past infections while also adapting to a changing pathogenic environment. Critical to the role of CRISPR as an adaptive immune mechanism is its capacity for self versus non-self recognition when acquiring novel immune memories. Yet, CRISPR systems vary widely in both how and to what degree they can distinguish foreign from self-derived genetic material. We document known and hypothesized mechanisms that bias the acquisition of immune memory towards non-self targets. We demonstrate that diversity is the rule, with many widespread but no universal mechanisms for self versus non-self recognition.

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.

BACKGROUND: 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.

Network-Based Prediction of Novel CRISPR-Associated Genes in Metagenomes.

A diversity of clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems provide adaptive immunity to bacteria and archaea through recording "memories" of past viral infections. Recently, many novel CRISPR-associated proteins have been discovered via computational studies, but those studies relied on biased and incomplete databases of assembled genomes. We avoided these biases and applied a network theory approach to search for novel CRISPR-associated genes by leveraging subtle ecological cooccurrence patterns identified from environmental metagenomes. We validated our method using existing annotations and discovered 32 novel CRISPR-associated gene families. These genes span a range of putative functions, with many potentially regulating the response to infection.IMPORTANCE Every branch on the tree of life, including microbial life, faces the threat of viral pathogens. Over the course of billions of years of coevolution, prokaryotes have evolved a great diversity of strategies to defend against viral infections. One of these is the CRISPR adaptive immune system, which allows microbes to "remember" past infections in order to better fight them in the future. There has been much interest among molecular biologists in CRISPR immunity because this system can be repurposed as a tool for precise genome editing. Recently, a number of comparative genomics approaches have been used to detect novel CRISPR-associated genes in databases of genomes with great success, potentially leading to the development of new genome-editing tools. Here, we developed novel methods to search for these distinct classes of genes directly in environmental samples ("metagenomes"), thus capturing a more complete picture of the natural diversity of CRISPR-associated genes.

Role of medial hypothalamic orexin system in panic, phobia and hypertension.

Orexin has been implicated in a number of physiological functions, including arousal, regulation of sleep, energy metabolism, appetitive behaviors, stress, anxiety, fear, panic, and cardiovascular control. In this review, we will highlight research focused on orexin system in the medial hypothalamic regions of perifornical (PeF) and dorsomedial hypothalamus (DMH), and describe the role of this hypothalamic neuropeptide in the behavioral expression of panic and consequent fear and avoidance responses, as well as sympathetic regulation and possible development of chronic hypertension. We will also outline recent data highlighting the clinical potential of single and dual orexin receptor antagonists for neuropsychiatric conditions including panic, phobia, and cardiovascular conditions, such as in hypertension.

Linking high GC content to the repair of double strand breaks in prokaryotic genomes.

Genomic GC content varies widely among microbes for reasons unknown. While mutation bias partially explains this variation, prokaryotes near-universally have a higher GC content than predicted solely by this bias. Debate surrounds the relative importance of the remaining explanations of selection versus biased gene conversion favoring GC alleles. Some environments (e.g. soils) are associated with a high genomic GC content of their inhabitants, which implies that either high GC content is a selective adaptation to particular habitats, or that certain habitats favor increased rates of gene conversion. Here, we report a novel association between the presence of the non-homologous end joining DNA double-strand break repair pathway and GC content; this observation suggests that DNA damage may be a fundamental driver of GC content, leading in part to the many environmental patterns observed to-date. We discuss potential mechanisms accounting for the observed association, and provide preliminary evidence that sites experiencing higher rates of double-strand breaks are under selection for increased GC content relative to the genomic background.

Visualization and prediction of CRISPR incidence in microbial trait-space to identify drivers of antiviral immune strategy.

Bacteria and archaea are locked in a near-constant battle with their viral pathogens. Despite previous mechanistic characterization of numerous prokaryotic defense strategies, the underlying ecological drivers of different strategies remain largely unknown and predicting which species will take which strategies remains a challenge. Here, we focus on the CRISPR immune strategy and develop a phylogenetically-corrected machine learning approach to build a predictive model of CRISPR incidence using data on over 100 traits across over 2600 species. We discover a strong but hitherto-unknown negative interaction between CRISPR and aerobicity, which we hypothesize may result from interference between CRISPR-associated proteins and non-homologous end-joining DNA repair due to oxidative stress. Our predictive model also quantitatively confirms previous observations of an association between CRISPR and temperature. Finally, we contrast the environmental associations of different CRISPR system types (I, II, III) and restriction modification systems, all of which act as intracellular immune systems.

Conditioned stimuli affect ethanol-seeking by female alcohol-preferring (P) rats: the role of repeated-deprivations, cue-pretreatment, and cue-temporal intervals.

RATIONALE: Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors. OBJECTIVES: The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking. METHODS: Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS- associated with the absence of EtOH (extinction training), and a neutral stimulus (CS0) presented in a neutral non-drug-paired environment. The rats underwent four deprivation cycles or were non-deprived, following extinction they were maintained in a home cage for an EtOH-free period, and then exposed to no cue, CS+, CS-, or CS0 to assess the effect of the conditioned cues on EtOH-seeking behavior. RESULTS: Repeated deprivations enhanced and prolonged the duration of CS+ effects on EtOH-seeking. Presentation of the CS- in a non-drug-paired environment blocked the ability of a CS+ to enhance EtOH-seeking in a drug-paired environment. Presentation of the CS+ or CS- in a non-drug-paired environment 2 or 4 h earlier significantly altered EtOH-seeking. CONCLUSION: Results indicated an interaction between repeated deprivation cycles and CS+ resulted in a potentiation of CS+ evoked EtOH-seeking. In addition, a CS- may have therapeutic potential by providing prophylactic protection against relapse behavior in the presence of cues in the drug-using environment.

Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels.

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.

Select panicogenic drugs and stimuli induce consistent increases in tail skin flushes and decreases in core body temperature.

Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the α2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9°C) increase in tail skin temperature and delayed decreases (~1-3°C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder.