Biology subjects

Grady, S. M.

Publications and source records attributed to Grady, S. M..

3 recordsLinked to original sources

bioRxiv2020

Electrophysiological signatures of acute systemic lipopolysaccharide: potential implications for delirium science

BackgroundNovel preventive therapies are needed for postoperative delirium, which especially affects aged patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity (SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signaling. MethodsEEG and cortical cytokine measurements (interleukin 6 [IL-6], monocyte chemoattractant protein-1 [MCP-1]) were obtained from adult and aged mice. Behavior, SWA, and functional connectivity (alpha-band weighted phase lag index) were assayed before and after systemic administration of lipopolysaccharide (LPS) +/- piroxicam (cyclooxygenase inhibitor) or caffeine (adenosine receptor antagonist). To avoid confounds from inflammation-driven changes in movement, which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching used to match distributions of movement magnitude between baseline and LPS. ResultsLPS produces increases in cortical cytokines and behavioral quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: {chi}2(4)=21.51, p=0.00057), but not connectivity ({chi}2(4)=6.39, p=0.17). Increases in SWA associate with IL6 (p<0.001) and MCP-1 (p=0.001) and are suppressed by piroxicam (p<0.001) and caffeine (p=0.046). Aged animals compared to adult show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence. ConclusionsCytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signaling may link inflammation to neural changes and hence delirium.

neuroscience↗

bioRxiv2020

Chronic Corticosterone Pretreatment Reverses Psilocybin Effects on Mouse Anxious and Hedonic Behaviors

Despite observed correlations between acute glucocorticoid release, self-reported anxiety, and long-term treatment outcomes for human studies using psilocybin-assisted psychotherapy approaches, the mechanistic relationship between psychedelic-dependent stress and subsequent behavioral responses remains unclear. Using rodents, direct manipulation of stress-associated hormone responses can be achieved with established pharmacologic models for the assessment of antidepressant and anxiolytic therapeutics. Here, chronic oral corticosterone-induced suppression of the hypothalamic-pituitary-adrenal axis is used to assess the relevance of drug-induced glucocorticoid release on the acute, post-acute, and long-term effects of psilocybin in male C57BL/6J mice. In these studies, psilocybin-induced acute anxiogenesis was found to be correlated to post-acute anxiolysis in a dose-dependent manner. Psilocybin also displayed acute increases in plasma corticosterone, but a post-acute anxiolytic effect in the novelty suppressed feeding test. Both effects were lost when psilocybin was administered in animals pre-exposed to chronic oral corticosterone. A similar long-term interaction between chronic corticosterone and psilocybin administration was observed in an open field test occurring one week after drug administration. Psilocybin administration alone led to more time spent in the center of the arena, but animals spent less time in the center with chronic corticosterone exposure. Intriguingly, these interactive effects were absent in animals exposed to brief isoflurane anesthesia after drug treatment. Overall, these experiments identify acute glucocorticoid release as a relevant biological modifier for the post-acute and long-term behavioral effects of psilocybin in mice. Rodent studies are thus suggested as a tractable means to address neuroendocrine mechanisms supporting context-dependent psychedelic effects in mammalian species.

animal behavior and cognition↗

bioRxiv2017

Evidence that loss of consciousness under anesthesia is not associated with impaired stimulus representation in auditory cortex

The mechanism whereby anesthetics cause loss of consciousness (LOC) is poorly understood. Current theories suggest that impaired representation of information in cortico-thalamic networks contributes to LOC under anesthesia. We sought to determine whether such changes are present in auditory cortex using information theoretic analysis of multiunit responses in rats. We tested the effects of three agents with different molecular targets: isoflurane, which acts at multiple pre- and postsynaptic loci, propofol, which acts primarily on GABAA receptors, and dexmedetomidine, an 2 adrenergic agonist. We reasoned that changes in the representation of sensory stimuli causative for LOC would be present regardless of the molecular target of the anesthetic. All three agents caused LOC, as assayed by the loss of righting reflex (LORR). We presented acoustic stimuli that varied across a wide range of temporal and spectral dynamics under control, sub-hypnotic (i.e. dose too low to cause LORR), just-hypnotic (a dose just sufficient to cause LORR) and recovery conditions. Changes in mutual information (MI) between the stimulus and spike responses under anesthesia diverged in two ways from predictions of a model in which stimulus representation is impaired upon LOC. First, the sign of changes in MI was agent-specific: MI increased under dexmedetomidine, while it decreased under isoflurane and propofol. Second, there was no consistent change in MI when transitioning from sub-hyptnotic to just-hypnotic doses: for none of the agents did MI decrease at the higher dose, and in some cases MI actually increased relative to the sub-hypnotic dose. Changes in MI under anesthesia were strongly correlated with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity. These data indicate that primary sensory cortex is not the locus for changes in information representation causative for LOC under anesthesia.

neuroscience↗