Neurogenesis dynamics in the olfactory bulb: deciphering circuitry organization, function, and adaptive plasticity.

ABSTRACT: Adult neurogenesis persists after birth in the subventricular zone, with new neurons migrating to the granule cell layer and glomerular layers of the olfactory bulb, where they integrate into existing circuitry as inhibitory interneurons. The generation of these new neurons in the olfactory bulb supports both structural and functional plasticity, aiding in circuit remodeling triggered by memory and learning processes. However, the presence of these neurons, coupled with the cellular diversity within the olfactory bulb, presents an ongoing challenge in understanding its network organization and function. Moreover, the continuous integration of new neurons in the olfactory bulb plays a pivotal role in regulating olfactory information processing. This adaptive process responds to changes in epithelial composition and contributes to the formation of olfactory memories by modulating cellular connectivity within the olfactory bulb and interacting intricately with higher-order brain regions. The role of adult neurogenesis in olfactory bulb functions remains a topic of debate. Nevertheless, the functionality of the olfactory bulb is intricately linked to the organization of granule cells around mitral and tufted cells. This organizational pattern significantly impacts output, network behavior, and synaptic plasticity, which are crucial for olfactory perception and memory. Additionally, this organization is further shaped by axon terminals originating from cortical and subcortical regions. Despite the crucial role of olfactory bulb in brain functions and behaviors related to olfaction, these complex and highly interconnected processes have not been comprehensively studied as a whole. Therefore, this manuscript aims to discuss our current understanding and explore how neural plasticity and olfactory neurogenesis contribute to enhancing the adaptability of the olfactory system. These mechanisms are thought to support olfactory learning and memory, potentially through increased complexity and restructuring of neural network structures, as well as the addition of new granule granule cells that aid in olfactory adaptation. Additionally, the manuscript underscores the importance of employing precise methodologies to elucidate the specific roles of adult neurogenesis amidst conflicting data and varying experimental paradigms. Understanding these processes is essential for gaining insights into the complexities of olfactory function and behavior.

Stroke risk in rheumatoid arthritis patients: exploring connections and implications for patient care.

Rheumatoid arthritis (RA) can independently increase the risk of stroke, affecting both young and adult RA patients. Recent attention has been drawn to the association between stroke and RA, supported by mounting evidence. Given that stroke is a significant and an urgent public health concern, this review aims to highlight the relationship between stroke and RA, covering mechanisms, underlying risk factors, early detection tools, and treatment implications. By uncovering the connection that links RA to stroke, we can pave the way for targeted healthcare practices and the development of preventive strategies for individuals with RA. Therefore, further research is imperative to deepen our understanding of this association and, ideally, guide treatment decisions for individuals at risk of both RA and stroke.

Significance of the anterior cingulate cortex in neurogenesis plasticity: Connections, functions, and disorders across postnatal and adult stages.

The anterior cingulate cortex (ACC) is a complex and continually evolving brain region that remains a primary focus of research due to its multifaceted functions. Various studies and analyses have significantly advanced our understanding of how the ACC participates in a wide spectrum of memory and cognitive processes. However, despite its strong connections to brain areas associated with hippocampal and olfactory neurogenesis, the functions of the ACC in regulating postnatal and adult neurogenesis in these regions are still insufficiently explored. Investigating the intricate involvement of the ACC in neurogenesis could enhance our comprehension of essential aspects of brain plasticity. This involvement stems from its complex circuitry with other relevant brain regions, thereby exerting both direct and indirect impacts on the neurogenesis process. This review sheds light on the promising significance of the ACC in orchestrating postnatal and adult neurogenesis in conditions related to memory, cognitive behavior, and associated disorders.

Cortical regulation of neurogenesis and cell proliferation in the ventral subventricular zone.

Neurogenesis and differentiation of neural stem cells (NSCs) are controlled by cell-intrinsic molecular pathways that interact with extrinsic signaling cues. In this study, we identify a circuit that regulates neurogenesis and cell proliferation in the lateral ventricle-subventricular zone (LV-SVZ). Our results demonstrate that direct glutamatergic projections from the anterior cingulate cortex (ACC), as well as inhibitory projections from calretinin+ local interneurons, modulate the activity of cholinergic neurons in the subependymal zone (subep-ChAT+). Furthermore, in vivo optogenetic stimulation and inhibition of the ACC-subep-ChAT+ circuit are sufficient to control neurogenesis in the ventral SVZ. Both subep-ChAT+ and local calretinin+ neurons play critical roles in regulating ventral SVZ neurogenesis and LV-SVZ cell proliferation.

Stoichiometric Post-Modification of Hydrogel Microparticles Dictates Neural Stem Cell Fate in Microporous Annealed Particle Scaffolds.

Microporous annealed particle (MAP) scaffolds are generated from assembled hydrogel microparticles (microgels). It has been previously demonstrated that MAP scaffold are porous, biocompatible, and recruit neural progenitor cells (NPCs) to the stroke cavity after injection into the stroke core. Here, the goal is to study NPC fate inside MAP scaffolds in vitro. To create plain microgels that can later be converted to contain different types of bioactivities, the inverse electron-demand Diels-Alder reaction between tetrazine and norbornene is utilized, which allows the post-modification of plain microgels stoichiometrically. As a result of adhesive peptide attachment, NPC spreading leads to contractile force generation which can be recorded by tracking microgel displacement. Alternatively, non-adhesive peptide integration results in neurosphere formation that grows within the void space of MAP scaffolds. Although the formed neurospheres do not impose a contractile force on the scaffolds, they are seen to continuously transverse the scaffolds. It is concluded that MAP scaffolds  can be engineered to either promote neurogenesis or enhance stemness depending on the chosen post-modifications of the microgels, which can be key in modulating their phenotypes in various applications in vivo.

Pharmacological Effect of GABA Analogues on GABA-ϱ2 Receptors and Their Subtype Selectivity.

GABAϱ receptors are distinctive GABAergic receptors from other ionotropic GABAA and metabotropic GABAB receptors in their pharmacological, biochemical, and electrophysiological properties. Although GABA-ϱ1 receptors are the most studied in this subfamily, GABA-ϱ2 receptors are widely distributed in the brain and are considered a potential target for treating neurological disorders such as stroke. The structure of GABA-ϱ2 receptors and their pharmacological features are poorly studied. We generated the first homology model of GABA-ϱ2 channel, which predicts similar major interactions of GABA with the binding-site residues in GABA-ϱ1 and GABA-ϱ2 channels. We also investigated the pharmacological properties of several GABA analogues on the activity of GABA-ϱ2 receptors. In comparison to their pharmacological effect on GABA-ϱ1 receptors, the activation effect of these ligands and their potentiation/inhibition impact on GABA response have interestingly shown inter-selectivity between the two GABA-ϱ receptors. Our results suggest that several GABA analogues can be used as research tools to study the distinctive physiology of GABA-ϱ1 and GABA-ϱ2 receptors. Furthermore, their partial agonist effect may hold promise for the future discovery of selective modulatory agents on GABAA receptors.

Roles of hydrophilic residues in GABA binding site of GABA-ρ1 receptor explain the addition/inhibition effects of competitive ligands.

The orthosteric binding site of GABA-gated ion channels has been widely explored. Many residues in the binding site of GABA were studied. The interactions due to the binding of GABA into the binding site drive channel activation and determine the potency and efficacy of GABA response. The combined effect of a competitive ligand and GABA on GABA-ρ1 receptors has been poorly studied. Here, we used point mutations, molecular modeling, and electrophysiological studies to explore the role of two hydrophilic residues (Serine 168 and Serine 243) of the GABA-ρ1 receptors in response to the binding of GABA and other studied ligands. Our results suggested that Ser168 residue stabilizes either closed state or open conformation depending on the other determinant interactions of each state. On the other hand, Ser243 residue is predicted to form different inter-subunit interactions with residues in the adjacent subunit at different states of the channel. Our current findings enlighten us to reasonably explain the additive/inhibitive effects of applying a competitive ligand with GABA simultaneously. Understanding the mixed effect of potentiation and inhibition would facilitate the discovery of new drugs to work as a direct GABA's activity modulators with more selectivity at various subunits forming GABA-gated ion channels.

Ligand modulation of KCNQ-encoded (KV7) potassium channels in the heart and nervous system.

KCNQ-encoded (KV7) potassium channels are diversely distributed in the human tissues, associated with many physiological processes and pathophysiological conditions. These channels are increasingly used as drug targets for treating diseases. More selective and potent molecules on various types of the KV7 channels are desirable for appropriate therapies. The recent knowledge of the structure and function of human KCNQ-encoded channels makes it more feasible to achieve these goals. This review discusses the role and mechanism of action of many molecules in modulating the function of the KCNQ-encoded potassium channels in the heart and nervous system. The effects of these compounds on KV7 channels help to understand their involvement in many diseases, and to search for more selective and potent ligands to be used in the treatment of many disorders such as various types of cardiac arrhythmias, epilepsy, and pain.

A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation.

KCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.

GABA-ρ receptors: distinctive functions and molecular pharmacology.

The homomeric GABA-ρ ligand-gated ion channels (also known as GABAC or GABAA -ρ receptors) are similar to heteromeric GABAA receptors in structure, function and mechanism of action. However, their distinctive pharmacological properties and distribution make them of special interest. This review focuses on GABA-ρ ion channel structure, ligand selectivity toward ρ receptors over heteromeric GABAA receptor sub-types and selectivity between different homomeric ρ sub-type receptors. Several GABA analogues show selectivity at homomeric GABA-ρ receptors over heteromeric GABAA receptors. More recently, some synthetic ligands have been found to show selectivity at receptors formed from one ρ subtype over others. The unique pharmacological profiles of these agents are discussed in this review. The classical binding site of GABA within the orthosteric site of GABA-ρ homomeric receptors is discussed in detail regarding the loops and residues that constitute the binding site. The ligand-residue interactions in this classical binding and those of mutant receptors are discussed. The structure and conformations of GABA are discussed in regard to its flexibility and molecular properties. Although the binding mode of GABA is difficult to predict, several interactions between GABA and the receptor assist in predicting its potential conformation and mode of action. The structure-activity relationships of GABA and structurally key ligands at ρ receptors are described and discussed.

The binding mode of picrotoxinin in GABAA-ρ receptors: Insight into the subunit's selectivity in the transmembrane domain.

The channel blocker picrotoxinin has been studied with GABAA-ρ1 and GABAA-ρ2 homology models based on the GluCl crystal structure. Picrotoxinin is tenfold more potent for GABAA-ρ2 than for GABAA-ρ1 homomeric channels. This intra-subunit selectivity arises from the unconserved residues at the 2' sites, which are the essential molecular basis for both the binding and potency of picrotoxinin. The serine residues at the 2' positions of the ρ2 channel are predicted to form multiple hydrogen bonds and hydrophobic interactions with picrotoxinin, whereas the proline residues in the 2' positions of ρ1 channels are predicted to form only hydrophobic contacts with picrotoxinin. However, although the studied ρ1 P2'G, A, and V models form no hydrogen bonds with picrotoxinin, they may participate in several hydrophobic interactions, and the ligand may have distinctive binding modes with GABAA-ρ mutant channels. Picrotoxinin has a lower Emodel value with ρ2 than ρ1 homomeric models (-47Kcal/mol and -36Kcal/mol, respectively), suggesting that picrotoxin blocks the pores of the ρ2 channels more effectively.

Investigating the Role of Loop C Hydrophilic Residue 'T244' in the Binding Site of ρ1 GABAC Receptors via Site Mutation and Partial Agonism.

The loop C hydrophilic residue, threonine 244 lines the orthosteric binding site of ρ1 GABAC receptors was studied by point mutation into serine, alanine and cysteine, and tested with GABA, some representative partial agonists and antagonists. Thr244 has a hydroxyl group essential for GABA activity that is constrained by the threonine methyl group, orienting it toward the binding site. Significant decreases in activation effects of the studied ligands at ρ1 T244S mutant receptors, suggests a critical role for this residue. Results of aliphatic and heteroaromatic partial agonists demonstrate different pharmacological effects at ρ1 T244S mutant receptors when co-applied with GABA EC50 responses. ρ1 T244A and ρ1 T244C mutant receptors have minimal sensitivity to GABA at high mM concentrations, whereas, the ρ1 WT partial agonists, ß-alanine and MTSEA demonstrate more efficacy and potency, respectively, than GABA at these mutant receptors. This study explores the role of Thr244 in the binding of agonists as an initial step during channel gating by moving loop C towards the ligand.

Comparison of templates for homology model of ρ1 GABAC receptors: More insights to the orthosteric binding site's structure and functionality.

Five sets of ρ1 GABAC homology models were generated based on X-ray crystal structures of the acetylcholine binding protein (AChBP), the ion channel from Caenorhabditis elegans (GLIC), the ion channel from Erwinia chrysanthemi (ELIC), the homomeric GABAA ß3 ion channel, and the homomeric α-subunit of glutamate-gated homopentameric chloride channel (GluCl). The GluCl based model was found to the represent the structure of ρ1 GABAC receptors. The GABA pose docked in the selected best model was confirmed by QM-polarized ligand docking and induced fit docking protocol, and used to study molecular interactions in the ρ1 GABA binding site. The potential interactions of identified residues are discussed. This study identified several residues with potential ligand interactions located on loops F and G with their side chain oriented toward the binding site such as Ser215 and Gln83. The partial agonists muscimol and imidazole-4-acetic acid (I4AA) were docked into the binding site of the most reliable 'GABA bound' homology model. The potency and efficacy of these partial agonists in activating recombinant ρ1 receptors were correlated with their docking results. The model predicts that muscimol resembles GABA in the docking pose with similar interactions. However, I4AA has a very different docking pose to GABA and was predicted by the model to form π-π stacking with aromatic residues in the orthosteric binding site. A set of TPMPA bound ρ1 homology models based on the GluClα 'apo state' template was built in order to study a competitive antagonist in the ρ1 orthosteric binding site. The results demonstrated the ability of our model to explain most experimental findings and predict potential roles of residues within the orthosteric binding site.

Target Based Designing of Anthracenone Derivatives as Tubulin Polymerization Inhibiting Agents: 3D QSAR and Docking Approach.

Novel anthracenone derivatives were designed through in silico studies including 3D QSAR, pharmacophore mapping, and molecular docking approaches. Tubulin protein was explored for the residues imperative for activity by analyzing the binding pattern of colchicine and selected compounds of anthracenone derivatives in the active domain. The docking methodology applied in the study was first validated by comparative evaluation of the predicted and experimental inhibitory activity. Furthermore, the essential features responsible for the activity were established by carrying out pharmacophore mapping studies. 3D QSAR studies were carried out for a series of 1,5- and 1,8-disubstituted10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-one derivatives for their antiproliferation activity. Based on the pattern recognition studies obtained from QSAR results, ten novel compounds were designed and docked in the active domain of tubulin protein. One of the novel designed compounds "N1" exhibited binding energy -9.69 kcal/mol and predicted Ki 78.32 nM which was found to be better than colchicine.