Biology subjects

Hon, O.

Publications and source records attributed to Hon, O..

4 recordsLinked to original sources

bioRxiv2024

Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system.

High intensity alcohol drinking during binge episodes overwhelmingly contributes to the socioeconomic burden created by Alcohol Use Disorders (AUD). Novel interventions are needed to add to the current therapeutic toolkit and nociceptin receptor (NOP) antagonists have shown promise in reducing heavy drinking days in patients with an AUD. However, an endogenous locus of nociceptin peptide and discrete sites of NOP action underlying this effect remains understudied. Here we show that the lateral septum (LS), a region contributing to binge drinking, is enriched in neurons expressing mRNA coding for the nociceptin peptide (Pnoc). Pnoc-expressing neurons of the LS (LSPnoc) are tuned to stimuli associated with negative valence and display increased excitability during withdrawal from binge-like alcohol drinking. LSPnoc activation was found to have aversive qualities and also potentiates binge-like drinking behavior, suggesting a convergence of circuitry that promotes aversion and drives alcohol consumption. Viral mediated tracing and functional assessment of LSPnoc projection fields revealed GABAergic synapses locally within the LS, and downstream within the lateral hypothalamus (LH) and supramammillary nucleus (SuM). Genetic deletion of NOP from the LS attenuated binge-like alcohol intake in male mice while NOP deletion from the LH and SuM decrease alcohol intake in females. Together, these findings are the first to demonstrate an endogenous population of nociceptin-expressing neurons that contributes to alcohol consumption and identifies sex-dependent modulation of alcohol drinking by NOP.

neuroscience↗

bioRxiv2023

Acute and chronic alcohol modulation of extended amygdala calcium dynamics

The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while increased stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.

neuroscience↗

bioRxiv2022

Serotonin Modulates an Inhibitory Input to the Central Amygdala from the Ventral Periaqueductal Gray

Fear is an adaptive state that drives defensive behavioral responses to specific and imminent threats. The central nucleus of the amygdala (CeA) is a critical site of adaptations that are required for the acquisition and expression of fear, in part due to alterations in the activity of inputs to the CeA. Here, we characterize a novel GABAergic input to the CeA from the ventral periaqueductal gray area (vPAG) using fiber photometry and ex vivo whole-cell slice electrophysiology combined with optogenetics and pharmacology. GABA transmission from this ascending vPAG-CeA input was enhanced by bath application of serotonin via activation of serotonin type 2C (5HT2C) receptors. Results indicate that these receptors are presynaptic. Interestingly, we found that GABA release from the vPAG-CeA input is enhanced following fear learning via activation of 5HT2C receptors and that this pathway is dynamically engaged during fear learning. Additionally, we characterized serotonin release in the CeA during fear learning and recall for the first time using fiber photometry coupled to a serotonin biosensor. Together, these findings describe a mechanism by which serotonin modulates GABA release from ascending vPAG GABA inputs to the CeA and characterize a role for this pathway in fear learning.

neuroscience↗

bioRxiv2018

Metformin Intervention Prevents Cardiac Dysfunction in a Murine Model of Adult Congenital Heart Disease

Congenital heart disease (CHD) is the most frequent birth defect worldwide and the number of adult patients with CHD, now referred to as ACHD, is increasing. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity and diabetes, is mostly unknown. Using a genetic mouse model of ACHD we showed that ACHD mice placed under metabolic stress (high fat diet) displayed decreased heart function. Comprehensive physiological, biochemical and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism that preceded cardiac dysfunction. Restoration of metabolic balance by metformin prevented the development of heart dysfunction in ACHD mice. This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure and may be an important avenue for intervention in ACHD.

genetics↗