Biology subjects

Suto, N.

Publications and source records attributed to Suto, N..

6 recordsLinked to original sources

bioRxiv2025

Food seeking suppression by environmental enrichment accompanies cell type- and circuit-specific prelimbic cortical modulation

Cues such as fast-food advertisements associated with food can provoke food cravings which may lead to unhealthy overeating. To effectively control such cravings, we need to better understand the factors that reduce food cue reactivity and reveal corresponding anti-craving brain mechanisms. We previously reported that access to environmental enrichment (EE) that provides cognitive and physical stimulation in mice reduced cue-evoked sucrose seeking and prelimbic cortex (PL) neuronal reactivity. To date, the phenotype of PL neurons that undergo EE-induced adaptations has not been fully elucidated. Therefore, we used brain slice electrophysiology to investigate how EE modulated intrinsic excitability in the general population of PL interneurons and pyramidal cells. Additionally, we used retrograde tracing and the neuronal activity marker Fos to investigate how EE modulated cue-evoked recruitment of pyramidal cells projecting to the paraventricular nucleus of the thalamus (PVT) and nucleus accumbens core (NAc). Before the cue-evoked sucrose seeking test, EE enhanced the general, baseline excitability of inhibitory interneurons, but not pyramidal cells, thereby promoting inhibitory overdrive. During cue-evoked sucrose seeking, EE suppressed recruitment of PVT-, but not NAc-projecting, neurons thereby selectively promoting corticothalamic, but not corticoaccumbens, excitatory underdrive. Collectively, we further illuminate EEs anti-food seeking actions whereby EE promotes both cell type-specific (inhibitory interneuron overdrive) and circuit-specific (excitatory corticothalamic underdrive) neuroadaptations in the PL.

neuroscience↗

bioRxiv2025

Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking

Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or neuronal ensembles in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify anti-craving relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of originally, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or excitatory overdrive. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting inhibitory underdrive. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory overdrive and inhibitory underdrive likely underlies EEs anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.

neuroscience↗

bioRxiv2025

Alcohol Use Disorder Associated Gene FNDC4 Alters Glutamatergic and GABAergic Neurogenesis

Large-cohort genome-wide association studies (GWAS) for alcohol use disorder (AUD) and AUD-related phenotypes have identified more than one hundred genetic loci. Functional study of those GWAS-identified loci might represent an important step toward understanding AUD pathophysiology. We found that genetic loci which are splicing quantitative trait loci (sQTLs) for the fibronectin III domain containing 4 (FNDC4) gene in the brain were identified by GWAS for both AUD drug treatment outcomes and AUD risk. However, FNDC4 function in the brain and how it might contribute to AUD pathophysiology remain unknown. In the present study, we characterized GWAS locus-associated FNDC4 splice isoforms, studies which suggested that FNDC4 alternative splicing results in loss-of-function for FNDC4. We also investigated FNDC4 function using CRISPR/cas9 gene editing, and the creation of human induced pluripotent stem cell (iPSC)-derived neural organoids joined with single-nucleus RNA sequencing. We observed that knock-out (KO) of FNDC4 resulted in a striking shift in the relative proportions of glutamatergic and GABAergic neurons in iPSC-derived neural organoids, suggesting a possible important role for FNDC4 in neurogenesis. We also explored potential mechanism(s) of FNDC4-dependent neurogenesis with results that suggested a role for FNDC4 in mediating neural cell-cell interaction. In summary, this series of experiments indicates that FNDC4 plays a role in regulating cerebral cortical neurogenesis in the brain. This regulation may contribute to the response to AUD pharmacotherapy as well as the effects of alcohol on the brain.

genomics↗

bioRxiv2025

Motivating Effects of Negative-hedonic Valence Encoded in Engrams

Engrams are neuronal alterations that encode associations between environmental contexts and subjectively rewarding or aversive experiences within sparsely activated neuronal assemblies that regulate behavioral responses. How positive- or negative-hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate or maladaptive behavior, respectively. It is well-known that animals avoid noxious stimuli and experiences. Little is known, however, how the conditioning of environmental or contextual stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations leading to compulsive maladaptive behavior. Here we have studied engrams that encode the conditioned effects of alcohol-related stimuli associated with the reversal of the dysphoric withdrawal state in alcohol dependent rats and document the recruitment of engrams in the paraventricular nucleus of the thalamus (PVT), the central nucleus of the amygdala (CeA), and the Dorsal Striatum (DS). The findings suggest that the encoding of associations between reversal of negative hedonic states and environmental contexts in these engrams may serve as a neural mechanism for compulsive alcohol seeking and vulnerability to relapse associated with dysregulation of reward to a pathological allostatic level.

neuroscience↗

bioRxiv2024

Inhibition of microtubule polymerization and dynein impairs the nuclear localization of the ependymoma-associated ZFTA-RELA fusion protein and NF-κB activation

Ependymomas are rare and chemotherapy-resistant gliomas. One subclass of supratentorial ependymomas, ST-EPN-ZFTA, expresses a fusion protein consisting of a nuclear protein, zinc finger translocation associated (ZFTA), and v-rel reticuloendotheliosis viral oncogene homolog A (RELA), an effector transcription factor of the nuclear factor-{kappa}B (NF-{kappa}B) pathway (ZFTA-RELA). Constitutive localization of ZFTA-RELA to the nucleus hyperactivates the oncogenic NF-{kappa}B signaling pathway, thereby contributing to the pathogenesis of ST-EPN-ZFTA. To identify compounds that inhibit NF-{kappa}B activity induced by ZFTA-RELA, we established a high-throughput screening system using the NF-{kappa}B-responsive luciferase reporter cell line 6E8, which expresses ZFTA-RELA in a doxycycline-dependent manner. A chemical library of 9600 compounds selected for their structural diversity was screened, and a colchicine derivative was identified. Among colchicine and six of its derivatives, the IC50 on ZFTA-RELA-dependent NF-{kappa}B-responsive luciferase activity in 6E8 cells was found to be the lowest for colchicine at 90 nM. Interestingly, microtubule polymerization inhibitors (colchicine and vinblastine) and dynein inhibitors (ciliobrevin D and dynarrestin) impaired ZFTA-RELAs nuclear localization and NF-{kappa}B activity in 6E8 cells. These findings indicate that microtubule polymerization and dynein play pivotal roles in activating the NF-{kappa}B pathway in ST-EPN-ZFTA by promoting the nuclear localization of ZFTA-RELA. Consequently, inhibition of microtubule polymerization may be a therapeutic strategy for ST-EPN-ZFTA.

cell biology↗

bioRxiv2024

Medial prefrontal cortical neurotransmitters reactive to relapse-promoting and relapse-suppressing cues in rats trained to self-administer cocaine or alcohol

Environmental cues conditioned to signal drug availability (S+) or omission (S-) activate specific neurons (neuronal ensembles/engram cells) within the medial prefrontal cortex (mPFC) to promote and suppress drug relapse in rats. However, the neurochemical source of such cue-specific activation remains unknown. In this study, we determined extracellular neurotransmitter fluctuations reactive to S+ vs. S- in the infralimbic (IL) and prelimbic (PL) cortices of male rats trained to lever-press for cocaine or alcohol self-administration. In cocaine- or alcohol-trained rats exposed to S+, no significant neurotransmitter fluctuations were observed in IL or PL. In cocaine-trained rats exposed to S-, glutamate, serotonin, taurine and adenosine were increased in PL but not in IL. In alcohol-trained rats exposed to S-, glutamate was increased, while dopamine and GABA were decreased, in IL but not in PL. Although S+ reactive neurotransmitters driving neuronal activation in mPFC remains to be elucidated, glutamate is likely the source of such activation by S- in rats trained to self-administer cocaine or alcohol. While drugs used for self-administration and cue-conditioning appear to dictate the type and anatomical specificity of S- evoked neurotransmission within mPFC, glutamate may serve as a common therapeutic target to mimic relapse-suppression by S- across cocaine and alcohol use disorders (CUD and AUD). In contrast, serotonin, taurine and adenosine may serve as the targets in CUD, while dopamine and GABA may serve as the targets in AUD.

neuroscience↗