Thalamic mediation of hypoxic respiratory depression in lambs

Abstract

Koos BJ, Rajaee A, Ibe B, Guerra C, Kruger L. Thalamic mediation of hypoxic respiratory depression in lambs. Am J Physiol Regul Integr Comp Physiol 310: R586 -R595, 2016. First published January 28, 2016 doi:10.1152/ajpregu.00412.2015.-Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53-80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development. brain; biphasic ventilation; hypoxia; respiratory inhibition; thalamus; sheep THE CRITICAL TRANSITION FROM fetus to newborn depends upon timely transfer of respiratory gas exchange from the placenta to lung and an essential change in respiratory control. In contrast to postnatal respiration, fetal breathing involves fluid-filled lungs, minimal pulmonary expansion, prolonged apneas, modulation by glycemia, independence of normal fluctuations in respiratory gases, expression limited to specific behavioral states, and inhibition by moderate hypoxia (47). Thus, parturitional changes critical for survival involve the onset of continuous breathing and hypoxic hyperpnea. Pioneering studies at Cambridge (5) and Oxford (20,21,39) revealed the uniqueness of the control of respiratory muscles in fetal sheep. The ovine model had considerable advantages in resistance to surgery-induced labor, and the large fetus facilitated instrumentation and measurement of blood gases and pH. This work and subsequent discoveries in sheep (e.g., Refs. 10,12,13,40,41,42,43,44,45,46,71,92) were instrumental in establishing the foundation for perinatal medicine.Immaturity of central respiratory controllers dispose newborns to recurrent apnea and thus O 2 deprivation. Respiratory responses to hypoxic stress include a rapid-onset stimulation (augmentation) followed by a gradual decline (depression). Putative O 2 sensors in the supramedullary brain stem (9, 52, 58, 81, 82, 90) mediate the depressant ...

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

“…Breathing‐modulated neurons are present in the thalamus (Chen, Eldridge, & Wagner, ). The parafascicular thalamic complex plays a role in hypoxia‐induced inhibition of breathing in the fetal brain (Koos et al, ; Koos, Rajaee, Ibe, Guerra, & Kruger, ). preBötC projections to the central medial thalamus, a region well connected to cortical, limbic, and sensorimotor structures including insular, anterior cingulate, somatosensory, and motor cortices, dorsal striatum, basolateral amygdala, nucleus accumbens, and basal ganglia (Vertes, Hoover, & Rodriguez, ), establishing a potential circuit to integrate breathing output with emotion and cognitive function.…”

Peri‐ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic‐clonic seizures

“…Correlational analyses indicated an association between hypoxia and volumes of specific sites that serve significant blood pressure and breathing roles: the posterior vermis, 18 thalamus, 7‐9 and hippocampus 19,20 . These sites exhibit volume loss in previous imaging studies of SUDEP and at‐risk populations, 1,2 as well as in other cohorts involving respiratory dysfunction 7 .…”

“…Intermittent hypoxic exposure results in neuronal injury to central structures that are essential for recovery from profound hypotension or apnea (eg, Purkinje cells and the fastigial nuclei of the cerebellum in rats) 6 . Conditions that lead to sustained and intermittent hypoxia, such as congenital central hypoventilation syndrome, lead to damage to the posterior thalamus, 7 an area that contributes to appropriate breathing in oxygen challenges, 8,9 as well as damage to the midbrain and cerebellar areas that mediate CO 2 responses 10 . Notably, both posterior thalamic gray matter volume loss and marked cerebellar injury appear in those who later have SUDEP and living patients at high risk 1 …”

Regional variation in brain tissue texture in patients with tonic-clonic seizures

“…The amygdala is the focus of processes that trigger apnea or respiratory rate through projections to the periaqueductal gray and parabrachial pons [ 26 ], and functional demonstrations by stimulation [ 28 ] or lesion evidence [ 29 ]. The ventral medial prefrontal cortex and hippocampal role in mediation of blood pressure has been well described [ 25 ], the posterior thalamus serves roles in mediating hypoxia and expiratory timing [ 34 , 35 ], and has shown tissue loss earlier [ 10 ], both dorsal and ventral medullary areas are critical in both chemo and lung afferent sensing for breathing and blood pressure, and the cerebellar deep nuclei play a significant role in compensating for extremes of both blood pressure loss or prolonged apnea [ 19 , 20 ].…”