Biology subjects

Kelly, M. N.

Publications and source records attributed to Kelly, M. N..

3 recordsLinked to original sources

bioRxiv2024

Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity

Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (LTF). Repetitive daily AIH (dAIH) exposure enhances phrenic LTF, demonstrating a form of metaplasticity. Two additional factors impacting phrenic LTF are age and sex. For example, moderate AIH-induced phrenic LTF decreases with age in males, but increases in middle-aged females. However, little is known concerning cellular mechanisms of dAIH effects or age-dependent sexual dimorphism in phrenic LTF. Moderate AIH elicits distinct signaling cascades within phrenic motor neurons initiated by 5HT2 receptors (Q pathway) versus adenosine 2A or 5HT7 receptors (S pathway), respectively. The Q and S pathways interact via mutual crosstalk inhibition, a powerful regulator of phrenic LTF. To test the hypothesis that dAIH, age and sex effects on phrenic LTF are associated with differential expression of molecules known to regulate the Q and S pathways, we assessed mRNA of key regulatory molecules in ventral cervical homogenates from spinal segments containing the phrenic motor nucleus from young (3 month) and middle-aged (12 month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules regulating the Q and/or S pathways, mRNA was correlated with serum estradiol. Rats (n=8/group) were exposed to sham (21% O2) or dAIH (15, 1 min episodes of 10.5% inspired O2 per day) for 14 days, and sacrificed 24 hours post-dAIH. mRNA for molecules known to regulate phrenic LTF were assessed via RT PCR, including: brain derived neurotrophic factor (Bdnf); serotonin 2A (Htr2a); 2B (Htr2b); and (Htr7) receptors; adenosine 2a (Adora2a) receptors; exchange protein activated by cAMP (Epac1); p38 MAP kinase [Mapk14 () & Mapk11 ({beta})]; PKA catalytic subunit (Prkaa1); PKA regulatory subunit (Prkar1a); fractalkine (Cx3cl1); phosphodiesterase type 4 (Pde4b); NAPDH-gp91 (Cybb) and p47 (ncf1); and the PKC{delta} isoform (Prkcd). Significantly higher Pde4b, Adora2a, and Prkcd mRNA were found in young and middle-aged females versus age-matched males; Epac1 was elevated, but only in young females (p<0.001). Ncf1 was increased in middle-aged versus young adult rats of both sexes (p<0.01). Ncf1, Cx3cl1, Adora2a and Prkcd mRNA were reduced by dAIH in middle-aged females (p<0.01), but not other groups. Serum estradiol levels positively correlated with Epac1 (r2=0.29, p=0.002), Mapk14 (r2=0.31, p=0.001), Mapk11 (r2=0.20, p=0.014), and Prkar1a (r2=0.20 p=0.013) mRNA. With higher serum estradiol levels, dAIH decreased Mapk14 mRNA (slope difference p=0.001). Thus, age, sex and dAIH preconditioning influence molecules known to regulate the Q and S pathways to phrenic motor facilitation. These novel findings advance our understanding of phrenic LTF, and inform translational research concerning the therapeutic potential of dAIH to treat breathing deficits in individuals of different ages or sex.

neuroscience↗

bioRxiv2022

Daily fluctuations in spinal adenosine determine mechanisms of respiratory motor plasticity

Plasticity is a fundamental property of the neuromotor system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity after exposure to intermittent low oxygen or acute intermittent hypoxia (AIH). pLTF can arise from distinct intracellular signaling cascades initiated by serotonin and adenosine; these cascades interact via powerful crosstalk inhibition. We demonstrate the serotonin/adenosine balance varies dramatically with time-of-day and details of the AIH protocol. Using a "standard" AIH protocol, the mechanism driving pLTF shifts from serotonin-dominant, adenosine-constrained during rest, to adenosine-dominant, serotonin-constrained in the active phase. This mechanistic flip results from daily changes in basal spinal adenosine levels across time-of-day combined with hypoxia-evoked spinal adenosine release. Since AIH is emerging as a promising therapeutic modality to restore respiratory (and non-respiratory) movements in people with spinal injury or ALS, new knowledge that time-of-day and protocol details impact mechanisms driving pLTF has experimental, biological and translational implications.

physiology↗

bioRxiv2018

Attention to a threat-related feature does not interfere with concurrent attentive feature selection

Visual features that are associated with a task and those that predict noxious events both prompt selectively heightened visuocortical responses. Conflicting views exist regarding how the competition between a task-related and a threat-related feature is resolved when they co-occur in time and space. Utilizing aversive differential Pavlovian conditioning, we investigated the visuocortical representation of two simultaneously presented, fully overlapping visual stimuli. Stimuli were isoluminant red and green random dot kinematograms (RDKs) which flickered at two tagging frequencies (8.57 Hz, 12 Hz) to elicit distinguishable steady-state visual evoked potentials (ssVEPs). Occasional coherent motion events prompted a motor response or predicted a noxious noise. These events occurred either in the green (task cue), the red (threat cue), or in both RDKs simultaneously. In an initial habituation phase, participants responded to coherent motion of the green RDK with a key press, but no loud noise was presented at any time. Here, selective amplification was seen for the task-relevant (green) RDK, but interference was observed when both RDKs simultaneously showed coherent motion. Upon pairing the threat cue with the noxious noise in the subsequent acquisition phase, the threat cue-evoked ssVEP (red RDK) was also amplified, but this amplification did not interact with amplification of the task cue, and did not alter the behavioral or visuocortical interference effect seen during simultaneous coherent motion. Results demonstrate that although competing feature conjunctions result in interference in visual cortex, the acquisition of a bias towards an individual threat-related feature does not result in additional cost effects.

neuroscience↗