It is suggested that Neu1-mediated PSA degradation may modulate dopamine D3 receptor-dependent nicotine sensitivity and contribute to reduced PSA levels and altered dopamine D3 receptor-related signaling, thereby influencing the threshold for nicotine-induced neural and behavioral activation.
Abstract
Nicotine induces pronounced neural and behavioral activation through dopaminergic signaling. However, the underlying molecular mechanisms that regulate nicotine sensitivity remain poorly understood. Here, we investigated the roles of lysosomal sialidase Neu1 and neural glycan polysialic acid (PSA) in nicotine-induced responses in zebrafish, a vertebrate model. Western blot analyses revealed reduced PSA levels and significantly upregulated neu1 expression in the zebrafish brain following acute nicotine exposure. Behavioral assays revealed increased tolerance to nicotine-induced lethality and attenuated nicotine-evoked swimming excitation in neu1-knockout (neu1-KO) zebrafish compared with those in wild-type fish. Nicotine-induced neuronal activation, assessed based on c-Fos expression, was markedly reduced in neu1-KO zebrafish. Gene expression analyses revealed altered dopaminergic signaling, including reduced drd3 expression, in neu1-KO zebrafish. Pharmacological experiments demonstrated that blocking dopamine D2/D3 receptors suppressed nicotine-induced swimming excitation in wild-type zebrafish, whereas treatment with a selective dopamine D3 receptor agonist partially rescued the attenuated nicotine responsiveness observed in neu1-KO zebrafish. Nicotine-induced c-Fos activation occurred predominantly in PSA-positive neurons within the hypothalamus, a brain region implicated in dopaminergic signaling. These findings suggest that Neu1-mediated PSA degradation may modulate dopamine D3 receptor-dependent nicotine sensitivity. We propose a conceptual model wherein nicotine-induced Neu1 activation may contribute to reduced PSA levels and altered dopamine D3 receptor-related signaling, thereby influencing the threshold for nicotine-induced neural and behavioral activation.
These findings identify ANO2 as a potential modulator of dopamine-related signaling and inhibitory behavioral control, expanding current understanding of calcium-activated chloride channel function in neural circuits relevant to behavioral domains implicated in neuropsychiatric disorders.
E. Cho, Jooeun Bae, J. Song et al.· Neuropsychopharmacology· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression by restoring neurotrophic signaling and dopaminergic function in the nucleus accumbens.
Kuan-Yin Tseng, Tung-Tai Kuo, Pi-Kai Chang et al.· Journal of Parkinson's Disea...· 0 citations
These findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Huanqing Yang, V. Kovářová, Alena O. Godunova et al.· Neurobiology of Stress· 0 citations
Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.
Shanglan Qu, Xin Peng, Jieyu Ji et al.· Frontiers in Pharmacology· 0 citations
Background Inflammation-associated depression is a subtype of major depressive disorder that is often resistant to conventional pharmacotherapies, which act in a regionally non-specific manner and therefore also produce unwanted side effects. Here we test GPR151, an orphan GPCR associated with inflammation and highly expressed in the habenula—a region linked to negative valence and depression—as a therapeutic target for inflammation-associated depression. Methods We integrated mouse and human habenular expression analyses with genetic loss-of-function and adult habenular re-expression approaches in mice. Gpr151 knockout mice and littermate controls were exposed to lipopolysaccharide (LPS) inflammatory challenge and assessed for stress coping and motivated behavior, body weight loss, and peripheral immune activation. To test whether adult habenular GPR151 expression is sufficient to restore inflammation-associated behavioral vulnerability, GPR151 was re-expressed in the habenula of knockout mice. Results GPR151 was exceptionally enriched in the habenula and showed conserved topographic organization and similar expression relationships with habenular marker genes in mice and humans. Following LPS challenge, male Gpr151 knockout mice showed reduced passive coping despite body weight loss and immune activation comparable to littermate controls. Adult habenular GPR151 re-expression increased LPS-induced amotivation in male knockout mice without increasing LPS-induced weight loss or immune activation. Female Gpr151 knockout mice also showed reduced passive coping after LPS challenge; however, habenular GPR151 re-expression was insufficient to increase LPS-induced amotivation in females. Conclusions These findings identify GPR151 as a conserved, regionally enriched regulator of behavioral sensitivity to inflammatory challenge and support GPR151 as a candidate therapeutic target for inflammation-associated depression.
Lupita Rios, You-Hsin Lin, Laura Yuan et al.· bioRxiv· 0 citations
