Biology subjects

Dorsey, S. G.

Publications and source records attributed to Dorsey, S. G..

3 recordsLinked to original sources

bioRxiv2023

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration revealed that VPA significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of genes associated with neurodevelopmental disorders (NDDs) such as autism as well as neurogenesis, axon growth and synaptogenesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 399 autism risk genes was significantly altered by VPA as was expression of 252 genes that have been reported to play fundamental roles in the development of the nervous system but are not otherwise linked to autism. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria provides potential targets for future hypothesis-driven approaches to elucidating the proximal underlying causes of defective brain connectivity in NDDs such as autism.

neuroscience↗

bioRxiv2021

Prolonged tonic pain in healthy humans enhances functional connectivity of descending pain modulation networks involving the amygdala, periaqueductal gray and parabrachial nucleus to cortical sensory-discriminative areas

IntroductionResting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC changes accompanying tonic pain in pain-free persons is rare. A brain network disrupted during chronic pain is a network we term the Descending Pain Modulatory Network (DPMN). Here, we evaluate the effect of tonic pain on FC of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). MethodsIn 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. We used functional MRI to measure resting BOLD signal during pain-free rest where participants experienced warmth and tonic pain where participants experienced the same temperature thermode combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity with FC during both states. We hypothesized tonic pain would disrupt FC dyads within the DPMN. We used partial correlation to determine FC correlated with pain intensity and BOLD signal. ResultsOf hypothesized FC dyads, PAG and subgenual ACC was weakly disrupted during tonic pain (F=3.34; p=0.074; pain-free>pain d=0.25). sgACC-PAG FC became positively related to pain intensity (R=0.38; t=2.81; p=0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R=0.44; t=3.43; p=0.001). During tonic pain, FC of this connection was abolished (paired t=-3.17; p=0.0026). During pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During tonic pain, FC between left AMYG and right inferior temporal and superior frontal gyri negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC and right claustrum; left and right primary visual cortex; right middle temporal gyrus and right temporo-occipitoparietal junction. Finally, subsequent pain positively correlated with PAG FC and left cerebellum, left dorsolateral prefrontal, right posterior cingulate cortex and paracentral lobule, inferior parietal lobule, medial precuneus and PBN. ConclusionWe demonstrate 1) tonic pain weakly disrupts of sgACC-PAG FC; 2) sgACC-PAG tonic pain FC positively correlates with pain; 3) right PBN-PAG FC predicts subsequent pain and is abolished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which predict intensity of tonic pain. Our findings suggest specific connectivity patterns within the DPMN at rest predict experienced pain and are modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation and biomarkers to guide interventions. HighlightsO_LIParabrachial-periaqueductal gray (PAG) functional connectivity (FC) predicts pain C_LIO_LISubgenual anterior cingulate cortex-PAG FC correlates with pain during tonic pain C_LIO_LIPAG- and amydalocortical networks at rest predict tonic pain intensity C_LIO_LIResting FC of PAG supports cortical targets of neuromodulation to control pain C_LI

neuroscience↗

bioRxiv2019

Prolonged tonic pain in healthy humans disrupts intrinsic brain networks implicated in pain modulation

Neural mechanisms of ongoing nociceptive processing in the human brain remain largely obscured by the dual challenge of accessing neural dynamics and safely applying sustained painful stimuli. Recently, pain-related neural processing has been measured using fMRI resting state functional connectivity (FC) in chronic pain patients. However, ongoing pain-related processing in normally pain-free humans remains incompletely understood. Therefore, differences between chronic pain patients and controls may be due to comorbidities with chronic pain. Decreased FC among regions of the descending pain modulation network (DPMN) are associated with presence and severity of chronic pain disorders. We aimed to determine if the presence of prolonged tonic pain would lead to disruption of the DPMN. High (10%) concentration topical capsaicin was combined with a warm thermode applied to the leg to create a flexible, prolonged tonic pain model to study the FC of brain networks in otherwise healthy, pain-free subjects in two separate cohorts (n=18; n=32). We contrasted seed-based FC during prolonged tonic pain with a pain-free passive task. In seed-based FC analysis prolonged tonic pain led to enhanced FC between the anterior middle cingulate cortex (aMCC) and the somatosensory leg representation. Additionally, FC was enhanced between the pregenual anterior cingulate cortex (pACC), right mediodorsal thalamus and the posterior parietal cortex bilaterally. Further, in the seed-driven PAG network, positive FC with the left DLPFC became negative FC during prolonged tonic pain. These data suggest that some altered DPMN FC findings in chronic pain could partially be explained by the presence of ongoing pain.

neuroscience↗