Biology subjects

Carr, G.

Publications and source records attributed to Carr, G..

4 recordsLinked to original sources

bioRxiv2025

Development of a Novel Benzodiazepine to Delineate Peripheral GABA-A Signaling Mechanisms in Visceral Pain Syndromes

Background and AimsVisceral pain is a cardinal symptom of many disorders affecting the gut. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate colonic pain but the specific contribution of peripheral GABAA receptors remains unclear as these agents have prominent central effects. MethodsUsing medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent benzodiazepine-based positive allosteric modulator (PAM) of GABAA receptors, Li633, with no significant central nervous system (CNS) penetration. ResultsThe locomotor activity of rats placed in an open field was unchanged with Li633 at doses up to 30 mg/kg, confirming its lack of a CNS effect. LI-633 produced robust potentiation of GABA-induced inward current, with EC50 values ranging from 8 nM (5{beta}2{gamma}2) to 128 nM (3{beta}2{gamma}2). In vitro electrophysiological studies confirmed its ability to reduce excitability of human dorsal root ganglion (DRG) neurons. LI-633 potentiated muscimol-induced GABAergic currents in rat DRG neurons in a dose-dependent manner, with an EC50 of 70.4 nM. In vivo, LI-633 significantly attenuated visceral hypersensitivity and pain behavior in a rat model of irritable bowel syndrome (IBS) and functional dyspepsia (FD). In the IBS model, administration of the drug also resulted in decreased excitability of colon-specific DRG neurons and significantly reduced the colonic afferent response to balloon distention as measured by recordings of neural activity in dorsal ganglia rootlets. ConclusionsThese findings highlight the potential of targeting peripheral GABAA receptors for pain management in IBS and other disorders associated with visceral hypersensitivity.

neuroscience↗

bioRxiv2024

Patterns of neural activity in prelimbic cortex neurons correlate with attentional behavior in the rodent continuous performance test

Sustained attention, the ability to focus on a stimulus or task over extended periods, is crucial for higher level cognition, and is impaired across multiple neuropsychiatric and neurodevelopmental disorders, including attention-deficit/hyperactivity disorder, schizophrenia, and depression. The rodent continuous performance test (rCPT) is a translational task that can be used to investigate the cellular mechanisms underlying sustained attention. Electrophysiological single unit and local field potential (LFPs) recordings reflect changes in neural activity in the prelimbic cortex (PrL) in mice performing sustained attention tasks. While evidence linking PrL neuronal activity to sustained attention is compelling, most studies have focused on single-cell activity surrounding behavioral responses, overlooking population-level dynamics across entire sessions that could offer additional insight into fluctuations in attention during task performance. Here, we used in vivo endoscopic calcium imaging to record patterns of neuronal activity in PrL neurons using the genetically encoded calcium sensor GCaMP6f in mice performing the rCPT at three timepoints characterized by differing levels of cognitive demand and task proficiency. We analyzed single-cell activity surrounding behavioral responses and population-level dynamics across sessions to determine how PrL neuronal activity evolves with sustained attention performance. A higher proportion of PrL neurons were recruited during correct responses in sessions requiring high task proficiency. Moreover, during rCPT sessions, mice intercalated responsive-engaged periods with non-responsive-disengaged periods. Applying a Hidden Markov Model (HMM) with two states to global PrL activity, we found neuronal states associated with task engagement. These states are characterized by different levels of correlated neuronal activity within PrL neurons. Overall, these findings illustrate that task proficiency, and task engagement differentially recruit activity in PrL neurons during a sustained attention task.

neuroscience↗

bioRxiv2023

Electrophysiological correlates of attention in the locus coeruleus - anterior cingulate cortex circuit during the rodent continuous performance test

Sustained attention, the ability to focus on an activity or stimulus over time, is significantly impaired in many psychiatric disorders, and there remains a major unmet need in treating impaired attention. Continuous performance tests (CPTs) were developed to measure sustained attention in humans, non-human primates, rats, and mice, and similar neural circuits are engaged across species during CPT performance, supporting their use in translational studies to identify novel therapeutics. Here, we identified electrophysiological correlates of attentional performance in a touchscreen-based rodent CPT (rCPT) in the locus coeruleus (LC) and anterior cingulate cortex (ACC), two inter-connected regions that are implicated in attentional processes. We used viral labeling and molecular techniques to demonstrate that neural activity is recruited in LC-ACC projections during the rCPT, and that this recruitment increases with cognitive demand. We implanted male mice with depth electrodes within the LC and ACC for local field potential (LFP) recordings during rCPT training, and identified an increase in ACC delta and theta power, and an increase in LC delta power during correct responses in the rCPT. We also found that the LC leads the ACC in theta frequencies during correct responses while the ACC leads the LC in gamma frequencies during incorrect responses. These findings may represent translational biomarkers that can be used to screen novel therapeutics for drug discovery in attention.

neuroscience↗

bioRxiv2019

Novel, non-nitrocatechol COMT inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility

Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel COMT inhibitors in a set of preclinical in vivo efficacy assays to determine their viability as potential clinical candidates. We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two dopamine metabolites, in cerebrospinal fluid (CSF) and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in a rat attentional set-shifting assay (ASST), an effect previously seen with the COMT inhibitor tolcapone. These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

neuroscience↗