Gary Cohen

Cardiorespiratory Anomalies in Mice Lacking CB1 Cannabinoid Receptors

Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage), or breathing (whole-body plethysmograph). Increases in arterial pressure and heart rate on passing from the light (rest) to the dark (activity) period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (β1) or vascular (α1) adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD.

The effect of growth hormone on sleep-related cardio-respiratory control in Prader-Willi syndrome.

Aim:  To evaluate the effects of growth hormone (GH) treatment on control of breathing, heart rate and blood pressure during sleep in Prader–Willi Syndrome (PWS).

A key circulatory defence against asphyxia in infancy - the heart of the matter!

•  A rise in heart rate boosts cardiac output and blood pressure, improves perfusion and oxygen delivery, and speeds recovery during an emergency. •  Breathing efforts and lung inflation reflexively elevate heart rate during experimental asphyxia, and may rescue (‘auto resuscitate’) an animal from imminent death. •  We analysed whether this mechanism elevates heart rate when a healthy, sleeping infant is confronted by mild, progressive asphyxia. •  Term‐born infants aged 1–8 days rebreathed the expired gas for short periods to stimulate breathing and heart rate but not arousal from sleep. •  We show that a rising CO2 level during asphyxia is much more strongly cardio‐acceleratory than either vigorous breathing efforts or lung inflation. •  This excitatory action of CO2 on the heart develops soon after birth. •  We suggest that (i) the hypercapnia during asphyxia helps raise heart rate; (ii) excitation by respiratory manoeuvres alone is relatively weak and short lived and may not produce the sustained heart rate rise needed to counteract circulatory depression.

Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency.

Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

Accurate discrimination of the wake-sleep states of mice using non-invasive whole-body plethysmography.

A major limitation in the study of sleep breathing disorders in mouse models of pathology is the need to combine whole-body plethysmography (WBP) to measure respiration with electroencephalography/electromyography (EEG/EMG) to discriminate wake-sleep states. However, murine wake-sleep states may be discriminated from breathing and body movements registered by the WBP signal alone. Our goal was to compare the EEG/EMG-based and the WBP-based scoring of wake-sleep states of mice, and provide formal guidelines for the latter. EEG, EMG, blood pressure and WBP signals were simultaneously recorded from 20 mice. Wake-sleep states were scored based either on EEG/EMG or on WBP signals and sleep-dependent respiratory and cardiovascular estimates were calculated. We found that the overall agreement between the 2 methods was 90%, with a high Cohen’s Kappa index (0.82). The inter-rater agreement between 2 experts and between 1 expert and 1 naïve sleep investigators gave similar results. Sleep-dependent respiratory and cardiovascular estimates did not depend on the scoring method. We show that non-invasive discrimination of the wake-sleep states of mice based on visual inspection of the WBP signal is accurate, reliable and reproducible. This work may set the stage for non-invasive high-throughput experiments evaluating sleep and breathing patterns on mouse models of pathophysiology.

Adverse circulatory effects of passive smoking during infancy: surprisingly strong, manifest early, easily avoided

To compare blood pressure reactions (BPR) of infants to mild stress for evidence of adverse cardiovascular effects of passive exposure to tobacco smoke during pregnancy and early infancy.

Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD)

ABSTRACT Autosomal dominant leukodystrophy (ADLD) is a rare adult‐onset demyelinating disease caused by overexpression of lamin B1, a nuclear lamina filament. Early autonomic dysfunction involving the cardiovascular system before progressive somatic motor dysfunction is a striking feature of most cases of ADLD. In the Plp‐FLAG‐LMNB1 transgenic mouse model, lamin B1 overexpression in oligodendrocytes elicits somatic motor dysfunction and neuropathology akin to ADLD. Here, we investigate whether Plp‐FLAG‐LMNB1 mice also develop autonomic cardiovascular dysfunction before or after somatic motor dysfunction. We find that Plp‐FLAG‐LMNB1 mice have preserved cardiovascular responses to changes in wake‐sleep state and ambient temperature and normal indexes of autonomic modulation at 37–42 weeks of age despite a progressive somatic motor dysfunction, which includes impairments of walking ability (the ability to walk on a narrow path was impaired in 80% of mice at 34–38 weeks of age) and subtle breathing derangements. Only late in the development of the disease phenotype did Plp‐FLAG‐LMNB1 mice develop a structural deficit of sympathetic noradrenergic fibers, with a 38% decrease in fiber profiles in the kidneys at 44–47 weeks of age. We demonstrate that while the Plp‐FLAG‐LMNB1 mouse model recapitulates the age‐dependent motor dysfunction of ADLD, it does not show signs of early autonomic cardiovascular dysfunction, raising the possibility that oligodendrocyte dysfunction may not be sufficient to cause the full spectrum of clinical features present in ADLD. HighlightsLamin B1 overexpression causes adult‐onset autosomal dominant leukodystrophy (ADLD).Age‐dependent motor dysfunction and early autonomic cardiovascular dysfunction are cardinal features of ADLD.Mice overexpressing lamin B1 in oligodendrocytes show age‐dependent motor dysfunction and a late loss of sympathetic fibers.However, these mice do not recapitulate the early autonomic cardiovascular dysfunction of ADLD.Lamin B1 overexpression in neurons or astrocytes may be key for the early development of autonomic cardiovascular dysfunction of ADLD.

Long-term cardiovascular reprogramming by short-term perinatal exposure to nicotine's main metabolite cotinine

Gather ‘proof‐of‐concept’ evidence of the adverse developmental potential of cotinine (a seemingly benign biomarker of recent nicotine/tobacco smoke exposure).

Prenatal nicotine exposure increases hyperventilation in α4-knock-out mice during mild asphyxia

Prenatal nicotine exposure alters breathing and ventilatory responses to stress through stimulation of nicotine acetylcholine receptors (nAChRs). We tested the hypothesis that α4-containing nAChRs are involved in mediating the effects of prenatal nicotine exposure on ventilatory and metabolic responses to intermittent mild asphyxia (MA). Using open-flow plethysmography, we measured ventilation (V̇(E)) and rate of O2 consumption ( V̇(O2)) of wild-type (WT) and α4-knock-out (KO) mice, at postnatal (P) days 1-2 and 7-8, with and without prenatal nicotine exposure (6 mg kg(-1) day(-1) beginning on embryonic day 14). Mice were exposed to seven 2 min cycles of mild asphyxia (10% O2 and 5% CO2), each interspersed with 2 min of air. Compared to WT, α4 KO mice had increased air V̇(E) and V̇(O2) at P7-8, but not P1-2. Irrespective of age, genotype had no effect on the hyperventilatory response (increase in V̇(E)/V̇(O2)) to MA. At P1-2, nicotine suppressed air V̇(E) and V̇(O2) in both genotypes but did not affect the hyperventilatory response to MA. At P7-8 nicotine suppressed air V̇(E) and V̇(O2) of only α4 KOs but also significantly enhanced V̇(E) during MA (nearly double that of WT; p<0.001). This study has revealed complex effects of α4 nAChR deficiency and prenatal nicotine exposure on ventilatory and metabolic interactions and responses to stress.