The Conditioning of Dyspneic Suffocation Fear

Mongeluzi, Donna L.; Rosellini, Robert A.; Ley, Ronald; Caldarone, Barbara J.; Stock, Howard S.

doi:10.1177/0145445503256316

Cited by 27 publications

(17 citation statements)

References 31 publications

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“…Freezing (an established measure of fear and panic-like behavior in rodents (8; 32)) was used to evaluate behavioral responses to CO 2 in TDAG8 +/+ /TDAG8 −/− mice. Following a CO 2 dose-response challenge, freezing was reduced in TDAG8 −/− mice relative to TDAG8 +/+ littermates on day 1 (Fig 2b).…”

Section: Resultsmentioning

confidence: 99%

“…Rising CO 2 concentrations lead to acidosis, creating a state of homeostatic imbalance resulting in defensive behavioral responses (6; 8; 32). CO 2 -evoked freezing is not completely attenuated in TDAG8 −/− mice, suggesting additional acid sensors (such as the acid-sensing ion channel 1 (ASIC1) in the amygdala (8) or acid sensing 5-HT neurons in the periaqueductal grey (36)) may also contribute.…”

Section: Discussionmentioning

confidence: 99%

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Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear

Vollmer

Ghosal

McGuire

et al. 2016

Biological Psychiatry

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Background Carbon dioxide (CO2) inhalation, a biological challenge and pathological marker in Panic Disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomical location of CO2-sensing systems that translate CO2-evoked fear remains unclear. We investigated contributions of microglial acid sensor T cell death associated gene-8 (TDAG8) and microglial pro-inflammatory responses in CO2-evoked behavioral and physiological responses. Methods CO2-evoked freezing, autonomic and respiratory responses were assessed in TDAG8-deficient (−/−) and wildtype (+/+) mice. Involvement of TDAG8-dependent microglial activation and pro-inflammatory cytokine IL-1β with CO2-evoked responses was investigated using microglial blocker, minocycline and IL-1β antagonist, IL- 1RA. CO2-chemosensitive firing responses using single-cell patch clamping were measured in TDAG8−/− and +/+ mice to gain functional insights. Results; TDAG8 expression was localized in microglia enriched within the sensory circumventricular organs (CVOs). TDAG8−/− mice displayed attenuated CO2-evoked freezing and sympathetic responses. TDAG8 deficiency was associated with reduced microglial activation and pro-inflammatory cytokine, IL-1β within the subfornical organ (SFO). Central infusion of microglial activation blocker, minocycline and IL-1β antagonist, IL-1RA attenuated CO2-evoked freezing. Finally, CO2-evoked neuronal firing in patch clamped SFO neurons was dependent on acid sensor TDAG8 and IL-1β. Conclusions Our data identify TDAG8-dependent microglial acid-sensing as a unique chemosensor for detecting and translating hypercapnia to fear-associated behavioral and physiological responses, providing a novel mechanism for homeostatic threat detection of relevance to psychiatric conditions such as panic disorder.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear

Vollmer

Ghosal

McGuire

et al. 2016

Biological Psychiatry

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“…The most prominent behavioral response evoked by CO 2 was immobility (freezing-like behavior), that was markedly different between strains. Previous reports of CO 2 inhalation in rats have reported freezing behavior using a similar concentration (Mongeluzi et al, 2003). 10% CO 2 also evokes freezing in mice as reported by our group (Vollmer et al, 2016), and others (Ziemann et al, 2009; Taugher et al, 2014, Liebold et al, 2016).…”

Section: Discussionmentioning

confidence: 72%

“…No comparison studies exist that have reported strain differences in CO 2 -evoked behavior. Previous studies have used SD or W rats in CO 2 inhalation paradigms (Mongeluzi et al, 2003; Dumont et al, 2010; Johnson et al, 2012; Schimitel et al, 2012). In agreement with our data, CO 2 inhalation (13%) did not affect immobility in Wistar rats (Schimitel et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Videos were scored by a trained observer blinded to genotype and treatment for total time spent immobile, as well as grooming and rearing frequency. Immobility, defined as the absence of all movement except for respiration, was our primary behavioral measure based on CO 2 -evoked fear behavior observed in previous studies from our group and others (Mongeluzi et al, 2003; Esquivel et al, 2010). Grooming included all bouts of facial and body grooming time.…”

Section: Methodsmentioning

confidence: 99%

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Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats

et al. 2017

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Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2 positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal grey (VLPAG) subdivision in CO2-sensitive strains. Conversely, DβH positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.

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The subfornical organ regulates acidosis‐evoked fear by engaging microglial acid‐sensor TDAG8 and forebrain neurocircuits in male mice

Winter

McMurray

Ahlbrand

et al. 2022

J of Neuroscience Research

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An important role of pH homeostasis has been suggested in the physiology of panic disorder, with acidosis as an interoceptive trigger leading to fear and panic. Identification of novel mechanisms that can translate acidosis into fear will promote a better understanding of panic physiology. The current study explores a role of the subfornical organ (SFO), a blood–brain barrier compromised brain area, in translating acidosis to fear‐relevant behaviors. We performed SFO‐targeted acidification in male, wild‐type mice and mice lacking microglial acid‐sensing G protein–coupled receptor—T‐cell death‐associated gene 8 (TDAG8). Localized SFO acidification evoked significant freezing and reduced exploration that was dependent on the presence of acid‐sensor TDAG8. Acidosis promoted the activation of SFO microglia and neurons that were absent in TDAG8‐deficient mice. The assessment of regional neuronal activation in wild‐type and TDAG8‐deficient mice following SFO acidification revealed significant acidosis and genotype‐dependent alterations in the hypothalamus, amygdala, prefrontal cortex, and periaqueductal gray nuclei. Furthermore, mapping of interregional co‐activation patterns revealed that SFO acidosis promoted positive hypothalamic‐cortex associations and desynchronized SFO‐cortex and amygdala‐cortex associations, suggesting an interplay of homeostatic and fear regulatory areas. Importantly, these alterations were not evident in TDAG8‐deficient mice. Overall, our data support a regulatory role of subfornical organ microglial acid sensing in acidosis‐evoked fear, highlighting a centralized role of blood–brain barrier compromised nodes in interoceptive sensing and behavioral regulation. Identification of pathways by which humoral information can modulate fear behavior is relevant to panic disorder, where aberrant interoceptive signaling has been reported.

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The Conditioning of Dyspneic Suffocation Fear

Cited by 27 publications

References 31 publications

Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear

Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear

Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats

The subfornical organ regulates acidosis‐evoked fear by engaging microglial acid‐sensor TDAG8 and forebrain neurocircuits in male mice

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