Respiratory manifestations of panic disorder in animals and humans: A unique opportunity to understand how supramedullary structures regulate breathing

Kinkead, Richard; Tenório, Luana Calcete Vaz; Drolet, Guy; Bretzner, Frédéric; Gargaglioni, Luciane H.

doi:10.1016/j.resp.2014.06.013

Cited by 27 publications

(17 citation statements)

References 124 publications

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“…However, given a strong stimulus, i.e., dyspnea or breathing distress, the resulting breathing‐related sensory signals could break through to higher cortical and limbic areas as a breathing sensation with an emotional valence, e.g., anxiety, panic. Moreover, direct signals from breathing CPG efferents to suprapontine regions could contribute to dysfunctions in the perception of breathing, e.g., breathlessness (Banzett et al, ; Davenport & Vovk, ; Kinkead, Tenorio, Drolet, Bretzner, & Gargaglioni, )…”

Section: Discussionmentioning

confidence: 99%

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Yang

Feldman

2018

J of Comparative Neurology

126

105

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The preBötzinger Complex (preBötC), a compact medullary region essential for generating normal breathing rhythm and pattern, is the kernel of the breathing central pattern generator (CPG). Excitatory preBötC neurons in rats project to major breathing-related brainstem regions. Here, we provide a brainstem connectivity map in mice for both excitatory and inhibitory preBötC neurons. Using a genetic strategy to label preBötC neurons, we confirmed extensive projections of preBötC excitatory neurons within the brainstem breathing CPG including the contralateral preBötC, Bötzinger Complex (BötC), ventral respiratory group, nucleus of the solitary tract, parahypoglossal nucleus, parafacial region (RTN/pFRG or alternatively, pF /pF ), parabrachial and Kölliker-Füse nuclei, as well as major projections to the midbrain periaqueductal gray. Interestingly, preBötC inhibitory projections paralleled the excitatory projections. Moreover, we examined overlapping projections in the pons in detail and found that they targeted the same neurons. We further explored the direct anatomical link between the preBötC and suprapontine brain regions that may govern emotion and other complex behaviors that can affect or be affected by breathing. Forebrain efferent projections were sparse and restricted to specific nuclei within the thalamus and hypothalamus, with processes rarely observed in cortex, basal ganglia, or other limbic regions, e.g., amygdala or hippocampus. We conclude that the preBötC sends direct, presumably inspiratory-modulated, excitatory and inhibitory projections in parallel to distinct targets throughout the brain that generate and modulate breathing pattern and/or coordinate breathing with other behaviors, physiology, cognition, or emotional state.

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Section: Discussionmentioning

confidence: 99%

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Yang

Feldman

2018

J of Comparative Neurology

126

105

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“…Primary among these are the amygdala, dorsomedial/perifornical hypothalamus and the periaqueductal gray, although other structures such as CVOs may also participate as chemosensitive sites. 107, 108 In fact, the concerted activity as well as, anatomical and functional links between rostral forebrain and brain stem structures is pertinent to panic attacks, where intense respiratory and psychological symptoms coexist. Figure 2 shows the localization of PD-relevant pH chemosensory targets, based on evidence derived from preclinical studies, and associated circuits that might contribute to panic responses.…”

Section: Ph Chemosensory Molecules and Their Relevance To Panic Pathomentioning

confidence: 99%

“…Focal lesions of the PAG do not alter ventilation during normocapnia, however, lead to reduced ventilatory responses to 7% CO 2. 107 There is now strong evidence that the dorsal PAG contains chemosensitive neurons that may be intrinsically sensitive to O 2 reduction, a hypoxia-sensitive alarm. Intravenous potassium cyanide, which produces anoxia, produced panic-like responses such as freezing and flight 147 and when paired with 8 or 13% CO 2 inhalation, enhances evoked flight responses and, independently facilitates the panic-like responses of rats during electrical PAG stimulation.…”

Section: Ph Chemosensory Molecules and Their Relevance To Panic Pathomentioning

confidence: 99%

Acid–base dysregulation and chemosensory mechanisms in panic disorder: a translational update

2015

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Panic disorder (PD), a complex anxiety disorder characterized by recurrent panic attacks, represents a poorly understood psychiatric condition which is associated with significant morbidity and an increased risk of suicide attempts and completed suicide. Recently however, neuroimaging and panic provocation challenge studies have provided insights into the pathoetiology of panic phenomena and have begun to elucidate potential neural mechanisms that may underlie panic attacks. In this regard, accumulating evidence suggests that acidosis may be a contributing factor in induction of panic. Challenge studies in patients with PD reveal that panic attacks may be reliably provoked by agents that lead to acid–base dysbalance such as CO2 inhalation and sodium lactate infusion. Chemosensory mechanisms that translate pH into panic-relevant fear, autonomic, and respiratory responses are therefore of high relevance to the understanding of panic pathophysiology. Herein, we provide a current update on clinical and preclinical studies supporting how acid–base imbalance and diverse chemosensory mechanisms may be associated with PD and discuss future implications of these findings.

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“…Neonatal maternal separation (NMS) is an established and clinically relevant model of stress that disrupts development of the cardiorespiratory control network through sex‐specific effects that persist into adulthood (Kinkead, Guertin, & Gulemetova, ; Kinkead, Tenorio, Drolet, Bretzner, & Gargaglioni, ; Rousseau et al., ). Respiratory measurements performed on 12‐day‐old rat pups, 2–4 h after the last bout of NMS, show that neonatal stress augments respiratory instability and apnoeas, especially in males (Gulemetova & Kinkead, ).…”

Section: Introductionmentioning

confidence: 99%

The influence of sex and neonatal stress on medullary microglia in rat pups

Baldy

Fournier

Boisjoly-Villeneuve

et al. 2018

Experimental Physiology

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Neonatal stress has wide-ranging consequences for the developing brain, including the medullary cardiorespiratory network. In rat pups, the reflexive cardiorespiratory inhibition triggered by the presence of liquids near the larynx is augmented by neonatal maternal separation (NMS), especially in males. Sex-specific enhancement of synaptic connectivity by NMS might explain this cardiorespiratory dysfunction. Microglia influence the formation, maturation, activity and elimination of developing synapses, but their role in the wiring of medullary networks is unknown. Owing to their sensitivity to sex hormones and stress hormones, microglial dysfunction could contribute to the abnormal cardiorespiratory phenotype observed in NMS pups. Here, we first used ionized calcium-binding adapter molecule-1 (Iba-1) immunolabelling to compare the density and morphology of microglia in the medulla of male versus female rat pups (14-15 days old) that were either undisturbed or subjected to NMS (3 h day ; postnatal days 3-12). Neonatal maternal separation augmented the density of Iba-1 cells (caudal region of the NTS), increased the size of the soma and reduced the arborization area (especially in the dorsal motor nucleus of the vagus). Sex-based differences were not observed. Given that the actions of microglia are regulated by neuronal fractalkine (CX CL ), we then used western blot analysis to compare the expression of CX CL and its microglial receptor (CX CR ) in medullary homogenates from control and NMS pups. Although CX CR expression was 59% greater in males versus females, NMS had no effect on CX CL /CX CR signalling. Given that an amoeboid morphology reflects an immature phenotype in developing microglia, NMS could interfere with synaptic pruning via a different mechanism.

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Respiratory manifestations of panic disorder in animals and humans: A unique opportunity to understand how supramedullary structures regulate breathing

Cited by 27 publications

References 124 publications

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Acid–base dysregulation and chemosensory mechanisms in panic disorder: a translational update

The influence of sex and neonatal stress on medullary microglia in rat pups

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