Biology subjects

Creasy, K. T.

Publications and source records attributed to Creasy, K. T..

4 recordsLinked to original sources

bioRxiv2024

VTA μ-opioidergic neurons facilitate low sociability in protracted opioid withdrawal

Opioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted withdrawal is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and mu-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTAMOR neurons in mediating protracted withdrawal-induced negative affect is not fully understood. In our study, we elucidate the role of VTAMOR neurons in mediating negative affect and altered brain-wide neuronal activities following opioid exposure and withdrawal in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted withdrawal. VTAMOR neurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knockout mice demonstrates that the disrupted social interaction observed during protracted withdrawal is facilitated by this neural population, without affecting other protracted withdrawal behaviors. Lastly, VTAMORs contribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTAMOR neurons as critical modulators of low sociability during protracted withdrawal and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid withdrawal. SIGNFICANCEThe compelling urge for relief from negative affective states during long-term opioid withdrawal presents a crucial challenge for maintaining abstinence. The ventral tegmental area (VTA) and its mu-opioid receptor-expressing (VTAMOR) neurons represent a critical target of opioidergic action that underlie dependence and withdrawal. Chronic activation of VTAMOR neurons during opioid exposure induces maladaptations within these neurons and their structurally connected circuitries, which alter reward processing and contribute to negative affect. Using an oral morphine drinking paradigm to induce dependence, we demonstrate that withdrawal engages VTAMOR neurons and identify this neuronal population as key mediators of opioid withdrawal-induced social deficits. These findings hold promise to inform development of targeted therapies aimed at alleviating negative affective states associated with protracted opioid withdrawal.

neuroscience↗

bioRxiv2024

Mimicking opioid analgesia in cortical pain circuits

The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, yet how opioid analgesics modulate this cortical circuit remains unclear. Uncovering how opioids alter nociceptive neural dynamics to produce pain relief is essential for developing safer and more targeted treatments for chronic pain. Here we show that a population of cingulate neurons encodes spontaneous pain-related behaviors and is selectively modulated by morphine. Using deep-learning behavioral analyses combined with longitudinal neural recordings in mice, we identified a persistent shift in cortical activity patterns following nerve injury that reflects the emergence of an unpleasant, affective chronic pain state. Morphine reversed these neuropathic neural dynamics and reduced affective-motivational behaviors without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic mu-opioid receptor promoter to drive chemogenetic inhibition. This opioid-mimetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management targeting a key nociceptive cortical opioid circuit with safe, on-demand analgesia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=40 SRC="FIGDIR/small/591113v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d294c0org.highwire.dtl.DTLVardef@123d4f4org.highwire.dtl.DTLVardef@1720deborg.highwire.dtl.DTLVardef@efc632_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

PPP1R3B is a metabolic switch that shifts hepatic energy storage from lipid to glycogen

Obesity is a growing worldwide epidemic that carries numerous metabolic complications including increased risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). Multiple genome-wide association studies (GWAS) have associated the PPP1R3B locus with cardiometabolic traits including fasting glucose and insulin levels (T2D traits), plasma lipids (CVD traits), and indications of hepatic steatosis and liver damage (NAFLD traits)1-5. The PPP1R3B gene encodes the glycogen regulatory protein PPP1R3B (also known as GL) which has an established role in liver glycogen metabolism and plasma glucose homeostasis6,7. The metabolic and NAFLD GWAS single nucleotide polymorphisms (SNPs) in this region, which are all in high linkage disequilibrium, result in increased liver PPP1R3B expression and hepatic glycogen accumulation, but have provided conflicting results on the impacts on hepatic steatosis and liver damage. Here we investigate the consequences of both Ppp1r3b overexpression and deletion in mouse and cell models and find that dysregulated Ppp1r3b expression in either direction promotes metabolic dysfunction and liver injury. Hepatocyte overexpression of Ppp1r3b increases hepatic glycogen storage, prolongs fasting blood glucose levels, and confers protection from hepatic steatosis, but increases plasma ALT in aged animals. Conversely, deletion of hepatocyte Ppp1r3b eliminates hepatic glycogen, causes impaired glucose disposal, and results in hepatic steatosis with age or high sucrose diet. We investigated the metabolic pathways contributing to steatosis and found that Ppp1r3b deletion and diminished glycogenesis diverts the storage of exogenous glucose to hepatic triglycerides (TG), and stored liver lipids are preferentially used for energy during fasting through lipid oxidation and ketogenesis. Further, we interrogated two large human biobank cohorts and found carriers of SNPs associated with increased PPP1R3B expression have increased plasma glucose, decreased hepatic fat, and lower plasma lipids, while putative loss-of-function (pLoF) variant carriers have increased hepatic fat and elevated plasma ketones and lipids, consistent with the results seen in our mouse models. These findings suggest hepatic PPP1R3B serves as a metabolic switch favoring hepatic energy storage as glycogen instead of TG.

molecular biology↗

bioRxiv2022

Elongation of Very Long Chain Fatty Acids Like- 3 (Elovl3) is activated by ZHX2 and is a regulator of cell cycle progression

Zinc fingers and homeoboxes 2 (ZHX2) functions as a tumor suppressor in several models of hepatocellular carcinoma (HCC), presumably through its control of target genes. Previous microarray data suggested that Elongation of Very Long Chain Fatty Acids 3 (Elovl3), a member of the Elovl family which synthesize very long chain fatty acids (VLCFAs), is a putative ZHX2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids, which are often dysregulated in diseases, including HCC. Since several previously identified ZHX2 targets become dysregulated in HCC, we investigated the relationship between ZHX2 and Elovl3 in liver damage and HCC. Here, using mouse and cell models, we demonstrate that Zhx2 positively regulates Elovl3 expression in the liver and that male-biased hepatic Elovl3 expression is established between 4-8 weeks of age in mice. Elovl3 is dramatically repressed in mouse models of liver regeneration and HCC and the reduced Elovl3 levels in the regenerating liver are associated with changes in hepatic very long chain fatty acids. Human hepatoma cell lines with forced Elovl3 expression have lower rates of cell growth; analysis of synchronized cells indicate that this reduced proliferation correlates with cells stalling in S-phase. Taken together, these data indicate that Elovl3 expression helps regulate cellular proliferation, possibly through control of VLCFAs, and its repression may be a contributing factor to HCC and explain, in part, the function of ZHX2 as a suppressor of HCC progression.

molecular biology↗