Biology subjects

Hess, E. M.

Publications and source records attributed to Hess, E. M..

3 recordsLinked to original sources

bioRxiv2025

PACAP Signaling Network in the Nucleus Accumbens Core Regulates Reinstatement Behavior in Rat

Cocaine use disorder (CUD) lacks FDA-approved treatments, partly due to the difficulty of creating therapeutics that target behavior-related neural circuits without disrupting signaling throughout the brain. Recent evidence highlights the therapeutic potential of targeting gut-brain axis components, such as GLP-1 receptors, to modulate neural circuits with minimal central nervous system disruption. Like GLP-1, pituitary adenylate cyclase polypeptide (PACAP) is a component of the gut-brain axis that regulates behavior through a network spanning the gut and brain. Here, we investigated the potential existence and function of an endogenous PACAP signaling network within the nucleus accumbens core (NAcc), which is a structure that integrates emotional, cognitive, and reward processes underlying behavior. We found that PACAP and its receptor, PAC1R, are endogenously expressed in the rat NAcc and that PACAP mRNA is present in medial prefrontal cortical projections to the NAcc. Behaviorally, intra-NAcc infusions of PACAP (100 pm) did not induce seeking behavior but blocked cocaine-primed reinstatement (10 mg/kg, IP). Intra-NAcc PACAP also inhibited reinstatement driven by co-infusion of the D1 receptor agonist (SKF 81297, 3 {micro}g) but not the D2 receptor agonist (sumanirole, 10 ng). These findings are significant since D1 and D2 receptor activities in the NAcc govern distinct behavioral mechanisms indicating precise actions of PACAP even within the NAcc. Future research should examine whether NAcc PACAP signaling can be selectively engaged by peripheral gut-brain axis mechanisms, potentially unveiling novel therapeutic approaches for CUD and related disorders.

neuroscience↗

bioRxiv2022

Genetic Disruption of System xc- Mediated Glutamate Release from Astrocytes Increases Negative-Outcome Behaviors While Preserving Basic Brain Function in Rat

The impact of CNS disorders is exacerbated by the difficulty in developing safe, effective glutamatergic therapeutics. Synaptic glutamate transmission is vital for neural physiology throughout the brain, which contributes to the vast therapeutic potential and safety risk of glutamatergic therapeutics. Here, we created a genetically modified rat (MSxc) to survey the range of brain functions impacted by the loss of glutamate release from astrocytes involving system xc- (Sxc). Eliminating Sxc activity was not lethal and did not alter growth patterns, activity states, novel object recognition or performance of other simple tasks. In contrast, MSxc rats differed from WT in Pavlovian Conditioned Approach and cocaine self-administration/reinstatement paradigms. Both WT and MSxc rats readily learned that a cue predicted food delivery during Pavlovian Conditioned Approach training. However, WT rats were more likely to approach the food tray (i.e., goal tracking) whereas MSxc rats were more likely to approach the food-predicted cue (i.e., sign tracking) even when this behavior was punished. In the self-administration/reinstatement paradigm, MSxc rats had higher levels of cocaine-primed drug seeking in the absence of altered extinction or cocaine self-administration. These data demonstrate that Sxc-mediated glutamate release from astrocytes regulates non-reinforced and negative-outcome behaviors without altering simple learning or other forms of basic brain function.

neuroscience↗

bioRxiv2021

MYCN mediates cysteine addiction and sensitizes to ferroptosis

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and irondependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.

cancer biology↗