Biology subjects

Vanderah, T. W.

Publications and source records attributed to Vanderah, T. W..

4 recordsLinked to original sources

bioRxiv2025

Molecular Dynamics in the Ventral Tegmental Area during Chronic Pain-Induced Negative Affect

Chronic pain frequently coexists with negative affect, with about 60% of patients suffering from both. This dual condition complicates treatment and exacerbates both disorders, highlighting the urgent need for innovative therapeutic strategies. Chronic pain negative affect (CPNA) involves complex neurobiological changes, including increased hyperexcitability of the ventral tegmental area (VTA), a critical region involved in reward, mood, and pain processing. To elucidate CPNAs underlying mechanisms, we employed a multidisciplinary approach using immunohistochemistry, lipidomic analysis, and proteomic screening to investigate VTA molecular alterations in mice subjected to partial sciatic nerve ligation (pSNL) at one and four weeks post-injury. Our results revealed a significant, sex-dependent increase in Kv7.2 channel expression in dopamine neurons, alongside a notable reduction in endocannabinoid 2-arachidonoylglycerol (2-AG) levels, which plays a vital role in mood regulation. This neurochemical shift associated with an increase in negative affect-like behaviors, as determined by the forced swim test. Furthermore, pharmacological intervention utilizing either exogenous 2-AG or retigabine, a Kv7 channel opener, effectively alleviated pain-related negative affect symptoms. Proteomic profiling further uncovered alterations within the CaMKK2 pathway, involving crucial proteins such as PLC{gamma}2, AMPK{gamma}2, and AMPK{beta}1, and CaMK1, with changes in abundance and phosphorylation activity that could be reversed with the next-generation CaMK1 antagonist CS640. This research provides the first comprehensive analyses of VTA adaptations linked to CPNA, yielding significant insights into molecular changes impacting VTA neuronal integrity and signaling throughout CPNA progression.

neuroscience↗

bioRxiv2023

The Role of Ryanodine Receptor 2 in Drug-Associated Learning

Type-2 ryanodine receptor (RyR2) ion channels facilitate the release of Ca2+ from stores and serve an important function in neuroplasticity. The role for RyR2 in hippocampal-dependent learning and memory is well established and chronic hyperphosphorylation of RyR2 (RyR2P) is associated with pathological calcium leakage and cognitive disorders, including Alzheimers disease. By comparison, little is known about the role of RyR2 in the ventral medial prefrontal cortex (vmPFC) circuitry important for working memory, decision making, and reward seeking. Here, we evaluated the basal expression and localization of RyR2 and RyR2P in the vmPFC. Next, we employed an operant model of sucrose, cocaine, or morphine self-administration (SA) followed by a (reward-free) recall test, to reengage vmPFC neurons and reactivate reward-seeking and re-evaluated the expression and localization of RyR2 and RyR2P in vmPFC. Under basal conditions, RyR2 was expressed in pyramidal cells but not regularly detected in PV/SST interneurons. On the contrary, RyR2P was rarely observed in PFC somata and was restricted to a different subcompartment of the same neuron - the apical dendrites of layer-5 pyramidal cells. Chronic SA of drug (cocaine or morphine) and nondrug (sucrose) rewards produced comparable increases in RyR2 protein expression. However, recalling either drug reward impaired the usual localization of RyR2P in dendrites and markedly increased its expression in somata immunoreactive for Fos, a marker of highly activated neurons. These effects could not be explained by chronic stress or drug withdrawal and instead appeared to require a recall experience associated with prior drug SA. In addition to showing the differential distribution of RyR2/RyR2P and affirming the general role of vmPFC in reward learning, this study provides information on the propensity of addictive drugs to redistribute RyR2P ion channels in a neuronal population engaged in drug-seeking. Hence, focusing on the early impact of addictive drugs on RyR2 function may serve as a promising approach to finding a treatment for substance use disorders.

neuroscience↗

bioRxiv2023

Kv7 Channel Opener Retigabine Reduces Self-Administration of Cocaine but Not Sucrose in Rats

The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviors that can be modeled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that Kv7/KCNQ channels may contribute in the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drug is not known. Here, we tested the ability of retigabine (ezogabine), a Kv7 channel opener, to regulate instrumental behavior in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a CPP assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine-pretreatment attenuated the self-administration of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared to sucrose-SA, cocaine-SA was associated with reductions in the expression of the Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward specific reduction in SA behavior considered relevant for the study of long-term compulsive-like behavior and supports the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.

neuroscience↗

bioRxiv2019

Functional NHE1 Expression is Critical to Blood Brain Barrier Integrity and Sumatriptan Blood to Brain Uptake

Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG with limited impact on trigeminal ganglia or trigeminal nucleus caudalis suggesting in vitro observations may have a significance in vivo. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.

neuroscience↗