The Cerebellar Fastigial Nucleus Contributes to CO\u3csub\u3e2\u3c/sub\u3e-H\u3csup\u3e+\u3c/sup\u3e Ventilatory Sensitivity in Awake Goats

The purpose of this study was to test the hypothesis that an intact cerebellar fastigial nucleus (CFN) is an important determinant of CO2-H+ sensitivity during wakefulness. Bilateral, stainless steel microtubules were implanted into the CFN (N = 9) for injection (0.5–10 μl) of the neurotoxin ibotenic acid. Two or more weeks after implantation of the microtubules, eupneic breathing and CO2-H+ sensitivity did not differ significantly (P \u3e 0.10) from pre-implantation conditions. Injection of ibotenic acid (50 mM) did not significantly alter eupneic PaCO2 (P \u3e 0.10). The coefficient of variation of eupneic PaCO2 was 4.0 ± 0.6 and 3.7 ± 0.4% over the 2 weeks before and after the lesion, respectively. CO2-H+ sensitivity expressed as inspired ventilation/PaCO2 decreased from 2.15 ± 0.17 pre-lesion to 1.58 ± 0.26 l/(min mmHg) 3–6 days post-lesion (P \u3c 0.02, −27%). There was no significant (P \u3e 0.10) recovery of sensitivity between 7 and 10 days post-lesion. The lesion also increased (P \u3c 0.05) the day-to-day variability of this index by nearly 100%. When CO2 sensitivity was expressed as elevated inspired CO2/room air VI, values at 7%, but not 3 and 5% inspired CO2, were reduced and more variable (P \u3c 0.05) after the ibotenic acid injections. We conclude that during wakefulness, the CFN contributes relatively more to overall ventilatory drive at high relative to low levels of hypercapnia

Effects on Breathing of Agonists to μ-opioid or GABA\u3csub\u3eA\u3c/sub\u3e Receptors Dialyzed into the Ventral Respiratory Column of Awake and Sleeping Goats

Pulmonary ventilation (V̇I) in awake and sleeping goats does not change when antagonists to several excitatory G protein-coupled receptors are dialyzed unilaterally into the ventral respiratory column (VRC). Concomitant changes in excitatory neuromodulators in the effluent mock cerebral spinal fluid (mCSF) suggest neuromodulatory compensation. Herein, we studied neuromodulatory compensation during dialysis of agonists to inhibitory G protein-coupled or ionotropic receptors into the VRC. Microtubules were implanted into the VRC of goats for dialysis of mCSF mixed with agonists to either μ-opioid (DAMGO) or GABAA (muscimol) receptors. We found: (1) V̇I decreased during unilateral but increased during bilateral dialysis of DAMGO, (2) dialyses of DAMGO destabilized breathing, (3) unilateral dialysis of muscimol increased V̇I, and (4) dialysis of DAMGO decreased GABA in the effluent mCSF. We conclude: (1) neuromodulatory compensation can occur during altered inhibitory neuromodulator receptor activity, and (2) the mechanism of compensation differs between G protein-coupled excitatory and inhibitory receptors and between G protein-coupled and inotropic inhibitory receptors

State-Dependent and -Independent Effects of Dialyzing Excitatory Neuromodulator Receptor Antagonists into the Ventral Respiratory Column

Unilateral dialysis of the broad-spectrum muscarinic receptor antagonist atropine (50 mM) into the ventral respiratory column [(VRC) including the pre-Bötzinger complex region] of awake goats increased pulmonary ventilation (V̇i) and breathing frequency (f), conceivably due to local compensatory increases in serotonin (5-HT) and substance P (SP) measured in effluent mock cerebral spinal fluid (mCSF). In contrast, unilateral dialysis of a triple cocktail of antagonists to muscarinic (atropine; 5 mM), neurokinin-1, and 5-HT receptors does not alter V̇i or f, but increases local SP. Herein, we tested hypotheses that 1) local compensatory 5-HT and SP responses to 50 mM atropine dialyzed into the VRC of goats will not differ between anesthetized and awake states; and 2) bilateral dialysis of the triple cocktail of antagonists into the VRC of awake goats will not alter V̇i or f, but will increase local excitatory neuromodulators. Through microtubules implanted into the VRC of goats, probes were inserted to dialyze mCSF alone (time control), 50 mM atropine, or the triple cocktail of antagonists. We found 1) equivalent increases in local 5-HT and SP with 50 mM atropine dialysis during wakefulness compared with isoflurane anesthesia, but V̇i and f only increased while awake; and 2) dialyses of the triple cocktail of antagonists increased V̇i, f, 5-HT, and SP

The Effects of Lesions in the Dorsolateral Pons on the Coordination of Swallowing and Breathing in Awake Goats

The purpose of this retrospective study was to gain insight into the contribution of the dorsolateral pons to the coordination of swallowing and breathing in awake goats. In 4 goats, cannulas were chronically implanted bilaterally through the lateral (LPBN) and medial (MPBN) parabrachial nuclei just dorsal to the Kölliker–Fuse nucleus (KFN). After \u3e2 weeks recovery from this surgery, the goats were studied for 5½ h on a control day, and on separate days after receiving 1 and 10 μl injections of ibotenic acid (IA) separated by 1 week. The frequency of swallows did not change during the control and 1 μl IA studies, but after injection of 10 μl IA, there was a transient 65% increase in frequency of swallows (P \u3c 0.05). Under control conditions swallows occurred throughout the respiratory cycle, where late-E swallows accounted for 67.6% of swallows. The distribution of swallow occurrence throughout the respiratory cycle was unaffected by IA injections. Consistent with the concept that swallowing is dominant over breathing, we found that swallows increased inspiratory (TI) and expiratory (TE) time and decreased tidal volume (VT) of the breath of the swallow (n) and/or the subsequent (n + 1) breath. Injections of 10 μl IA attenuated the normal increases in TI and TE and further attenuated VT of the n breath. Additionally, E and I swallows reset respiratory rhythm, but injection of 1 or 10 μl IA progressively attenuated this resetting, suggesting a decreased dominance over respiratory motor output with increasing IA injections. Post mortem histological analysis revealed about 50% fewer (P \u3c 0.05) neurons remained in the KFN, LPBN, and MPBN in lesioned compared to control goats. We conclude that dorsolateral pontine nuclei have a modulatory role in a hypothesized holarchical neural network regulating swallowing and breathing particularly contributing to the normal dominance of swallowing over breathing in both rhythm and motor pattern generation

A Role for the Kolliker-Fuse Nucleus in Cholinergic Modulation of Breathing at Night During Wakefulness and NREM Sleep

For many years, acetylcholine has been known to contribute to the control of breathing and sleep. To probe further the contributions of cholinergic rostral pontine systems in control of breathing, we designed this study to test the hypothesis that microdialysis (MD) of the muscarinic receptor antagonist atropine into the pontine respiratory group (PRG) would decrease breathing more in animals while awake than while in NREM sleep. In 16 goats, cannulas were bilaterally implanted into rostral pontine tegmental nuclei (n = 3), the lateral (n = 3) or medial (n = 4) parabrachial nuclei, or the Kölliker-Fuse nucleus (KFN; n = 6). After \u3e2 wk of recovery from surgery, the goats were studied during a 45-min period of MD with mock cerebrospinal fluid (mCSF), followed by at least 30 min of recovery and a second 45-min period of MD with atropine. Unilateral and bilateral MD studies were completed during the day and at night. MD of atropine into the KFN at night decreased pulmonary ventilation and breathing frequency and increased inspiratory and expiratory time by 12–14% during both wakefulness and NREM sleep. However, during daytime studies, MD of atropine into the KFN had no effect on these variables. Unilateral and bilateral nighttime MD of atropine into the KFN increased levels of NREM sleep by 63 and 365%, respectively. MD during the day or at night into the other three pontine sites had minimal effects on any variable studied. Finally, compared with MD of mCSF, bilateral MD of atropine decreased levels of acetylcholine and choline in the effluent dialysis fluid. Our data support the concept that the KFN is a significant contributor to cholinergically modulated control of breathing and sleep

The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization