Biology subjects

Simandl, G.

Publications and source records attributed to Simandl, G..

5 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↗

bioRxiv2025

SYSTEM XC- AS A MOLECULAR MECHANISM FOR EVOLUTIONARY NEW FORMS OF ADVANCED COGNITION

Human cognitive abilities are deeply rooted in evolutionary building blocks that maximize computation while maintaining efficiency. These abilities are not without evolutionary signatures; conserved processes like vision have undergone continual phylogenetic adjustments to better serve ecological niches. Conversely, more sophisticated forms of cognition may have required evolutionary innovations to transform existing neuronal processing to expand computational abilities. One such innovation is system xc- (Sxc), a cystine-glutamate antiporter predominantly localized to astrocytes that emerged in deuterostomes (e.g., vertebrates) after their divergence from protostomes over 550 million years ago. Previous evidence suggests that genetically modified rats that lack functional Sxc (MSxc) exhibit enhanced cocaine-seeking behavior. In this study, we deconstructed drug-seeking into its component behaviors, categorizing them as reliant on evolutionary conserved or newly evolved cognitive processes. Our results reveal that Sxc function is dispensable for conserved processes like visual, emotional, and hedonic processing, but critical for advanced, evolutionary new cognitive functions, particularly impulse control and decision making. Notably, we demonstrate a temporally specific reliance on Sxc during the learning phase of optimal decision-making, but not in maintaining established strategies. This is an important addition to our current understanding of astrocytes in non-homeostatic functions, indicating their critical role in computationally demanding phases of learning and memory. Unraveling evolutionary innovations like Sxc not only deepens our understanding of cognitive evolution but also paves the way for revolutionary, precision- targeted therapies in neuropsychiatric disorders, potentially transforming treatment paradigms and patient outcomes.

neuroscience↗

bioRxiv2024

Cross-species modeling and enhancement of cognitive control with striatal brain stimulation

Brain disorders, particularly mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. We show a path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result, showing that DBS-like stimulation of the mid-striatum improves cognitive control in rats. Using this model, we identify a mechanism, improvement in domain-general cognitive control, and rule out competing hypotheses such as impulsivity. The rat findings explain prior human results and have immediate implications for clinical practice and future trial design. One Sentence Summary: Developing a reliable animal model of a human brain stimulation therapy reveals that this therapy works by enhancing the brains ability to process conflicting pieces of evidence.

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↗

bioRxiv2020

Lost in translation: No effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

BACKGROUNDThe orbitofrontal cortex-ventromedial striatum (OFC-VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. METHODS27 male Long-Evans rats implanted with optical-fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC-VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after and one hour after each stimulation, one and two weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC-VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional setshifting. RESULTSOFC-VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the mouse protocol did alter OFC-VMS synaptic weighting. CONCLUSIONSIn sum, although physiological changes were observed in the OFC-VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. If optogenetic effects on behavior do not reliably transfer between rodent species, this may have important implications for designing rodent-to-human translational pipelines.

neuroscience↗