Pharmacological inhibition of infralimbic prefrontal cortex abolishes sniffing behavior and respiratory response to stress
Authors: Bondarenko Evgeny , Nalivaiko Eugene 
Published: November 2023

IntroductionRespiration is a highly sensitive index of autonomic activation during stress. We have recently investigated the roles of the amygdala, the hypothalamus and the periaqueductal gray in the production of respiratory responses to brief and prolonged stressors in rats. In the current study we extend this investigation to the infralimbic prefrontal cortex (ilPFC). Out of all tested regions in the prefrontal cortex, stimulation of ilPFC evokes the greatest respiratory response in anesthetized rats (Hassan et al., 2013, J Physiol, 6069).MethodsRats (n=8) were implanted with bilateral guide cannulas targeting the ilPFC. On separate days, in a counter‐balanced design they were subjected to respiratory recording (plethysmography) sessions consisting of acclimatization/novelty stress, presentation of acoustic stimuli, presentation of light stimulus and restraint. Each animal completed the session twice – once after saline and once after muscimol (2nmol/200nl/side) microinjection.ResultsSubmission to novelty and restraint stress elevated basal respiratory rate, which gradually declined as the stress progressed. Inhibition of the ilPFC almost completely abolished this response (p < .043 for novelty; p < .047 for restraint). Additionally, ilPFC blockade almost completely abolished incidence of high‐frequency respiratory rate during both novelty and restraint stresses. Presentation of acoustic stimuli evoked transient changes in respiratory rate in an intensity‐dependent manner; these responses were significantly inhibited by ilPFC inactivation (all p < .043). Lastly, presentation of the light stimulus evoked exploratory behavior and sniffing in animals; while light stimulus after ilPFC inactivation evoked exploratory behavior without any sniffing (p = .002 for the difference in respiratory rate between muscimol and saline trials).ConclusionsThe effects of inactivation of ilPFC were almost identical to inactivation of the dorsomedial hypothalamic/perifornical area in our previous study (Bondarenko et al, 2015, AJP: Regu, 308, R816), suggesting that it is one of the major structures of the forebrain respiratory stress axis. ilPFC has extensive connections with other regions to perform this role: It receives input from the orbital prefrontal cortex, which integrates sensory information of different modalities. The efferent connections of the ilPFC include the hypothalamus, the amygdala, the periaqueductal gray and the nucleus of the solitary tract. Additionally, the ilPFC and the dorsally located prelimbic prefrontal cortex have been implicated in central cardiovascular control during stress (Resstel and Correa, 2006, Auton Neurosci, 126, 130). Our study therefore suggests that the ilPFC is one of the major components of the respiratory stress network. Its integrity is essential for stress‐induced increase in basal respiratory rate as well as for any transient respiratory arousal/sniffing.Support or Funding InformationThis study was supported by the National Heart Foundation of Australia