Cognitive impairment is a frequent but underrecognized complication of neurodegenerative and traumatic central nervous system disorders. Although research on Alzheimer's disease (AD) revealed that microglial triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in inhibiting neuroinflammation and improving cognition, its contribution to cognitive impairment following spinal cord injury (SCI) is unclear. Evidence from AD shows that TREM2 drives microglial activation, promotes pathological protein clearance, and disease-associated microglia (DAM) formation. SCI patients also experience declines in attention, memory, and other functions, yet the specific mechanism of these processes remains unclear. In SCI, microglia and TREM2 are involved in inflammation and repair, but their relationship with higher cognitive functions has not been systematically examined. We infer that TREM2 might connect injury-induced neuroinflammation in the SCI with cognitive deficits, providing a new treatment target. Artificial intelligence (AI) offers an opportunity to accelerate this endeavor by incorporating single-cell transcriptomics, neuroimaging, and clinical data for the identification of TREM2-related disorders, prediction of cognitive trajectories, and applications to precision medicine. Novel approaches or modalities of AI-driven drug discovery and personalized rehabilitation (e.g., VR, brain-computer interface) can more precisely steer these interventions. The interface between lessons learned from AD and SCI for generating new hypotheses and opportunities for translation.

Insulin-like growth factor-1 (IGF-1) is a single chain polypeptide hormone that plays an essential role in intrauterine and postnatal growth. Recent studies suggest that IGF-1 and its receptor IGF-1R are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IGF-1 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. We found that the expression levels of IGF-1 were markedly enhanced in astrocytes post HI. Delivery of IGF-1 significantly alleviates neonatal brain insult and improves neurobehavioral disorders in neonatal mice after HI challenge. Through binding to IGF-1 receptor (IGF-1R), IGF-1 inhibited the apoptosis of neuronal cells following HI exposure. IGF-1 improved neuronal cell survival and proliferation through activation of phosphorylated AKT signaling. Of note, the protective property of IGF-1 against ischemic neuronal insults was dependent on suppression of the FoXO3a-PUMA signaling pathway. Taken together, these findings suggest that IGF-1 may represent a new neuroprotectant for newborns with hypoxic-ischemic encephalopathy.

Vesicular monoamine transporter 2 (VMAT-2) plays a vital role in packaging cytosolic monoamine transmitters into axon terminal vesicles, which can be released in response to action potentials. Reserpine (RSP), a classical irreversible inhibitor of the monoamine transporter, is an alkaloid used as an antihypertensive drug. However, its use in medicine was very short-lived because of side effects (depression, Parkinsonism). Tetrabenazine (TBZ) and valbenazine (VBZ), biochemically non-competitive and reversible VMAT-2 inhibitors, are both used in the treatment of Tardive Dyskinesia (TD). The aim of this study was to directly compare the effects of RSP, TBZ, and VBZ on vesicular storage and exocytotic release of monoamines in hippocampal slices, and to clarify whether their actions differ in terms of reversibility and persistence. Our work addresses the biological question of how these clinically relevant VMAT-2 inhibitors modulate monoaminergic neurotransmission at the synaptic level.

Dopamine released from the axon terminals of dopaminergic neurons is central to behaviors like reward learning and complex motor output. The dynamic control of dopamine release canonically occurs through two main mechanisms: the modulation of somatic excitability and the regulation of vesicular release at presynaptic boutons. However, there is also a third mechanism: the precise and local control of axonal excitability. Together, these three mechanisms control the amplitude and timing of dopamine release from terminal axons. In this review, we examine the intrinsic properties and dynamic modulation of dopaminergic axons. First, we will examine their intrinsic properties, including membrane biophysics and morphological features. Second, we will focus on the modulation of axonal excitability through receptor signaling. Finally, we will review how drugs of abuse directly influence axonal physiology, and how axonal excitability influences the progression and etiology of Parkinson's disease. Through this review we hope to highlight the important role that modulation of axonal excitability plays in controlling dopamine release, beyond action potential propagation.

Cognitive impairments associated with schizophrenia (CIAS) include deficits in declarative memory. This is associated with an inability to maintain information in short-term memory when distracted, and increased sensitivity to proactive interference. These CIAS may partly result from decreased expression of parvalbumin (PV) in medial prefrontal cortex (mPFC) interneurons. The sub-chronic phencyclidine (scPCP) rodent is a widely used model for schizophrenia that recapitulates CIAS, including declarative memory, social cognition and mPFC PV deficits. Thus, distraction before the test phase in novel object recognition (NOR) produces robust declarative memory deficits in scPCP rats. Controlling for distraction in the single trial or continuous NOR paradigm (cNOR) protects memory recall, and multi-trial cNOR reveals increased sensitivity to proactive interference for object memory. Here, we sought to expand scPCP model cross-species validity by comparing these NOR/cNOR deficits across scPCP rats and mice. We then aimed to determine whether distraction-dependent deficits are conserved across object and social memory domains in scPCP mice, assessing sociability and social memory using automated mouse tracking to sub-classify social interaction behaviors.

Studies indicate that pattern separation for spatial and object information involves structures of the temporal cortex (lateral entorhinal and perirhinal cortices) and hippocampus (dentate gyrus and CA3), which are particularly sensitive to aging. However, little is known about how the hippocampal network, the anteroposterior axis of these regions, and the excitatory-inhibitory circuit contribute to the recognition and separation of object patterns.

Mutations in the gene () cause non-syndromic hearing impairment, with congenital (DFNB10) or late childhood onset (DFNB8). In some reports, these patients were found to have lower speech comprehension scores with cochlear implants (CIs) compared to CI users with other etiologies. Since CIs electrically stimulate spiral ganglion neurons (SGNs) to activate the auditory pathway, TMPRSS3 deficiency was presumed to cause a dysfunction or degeneration of these cells, of which type I SGNs form the predominant group. Here, we revisited the expression pattern of in the developing and mature mouse inner ear on mRNA level with quantitative few-cell PCR and RNAscope, and on protein level with immunohistochemistry with an anti-TMPRSS3 antibody validated on knock-out tissue. In the organ of Corti, we demonstrate expression of in inner and outer hair cells, particularly in the stereocilia, and in pillar cells. Furthermore, expression of this gene in root cells of the lateral wall close to the stria vascularis indicates a potential function in K recycling, and expression in the spiral limbus may be linked to the generation of the tectorial membrane. Within Rosenthal's canal, in immature tissue, was diffusely expressed in all SGNs, but in the mature ear, in type I SGNs we found only minor mRNA amounts with qPCR, RNAscope, and no specific immunolabeling. In contrast, in type II SGNs expression is enhanced during maturation. We hypothesize that the background levels of expression in type I SGNs are not directly responsible for the vitality of these neurons, and that indirect effects, like signaling cascades dependent on TMPRSS3 in other cell types, are crucial for type I SGN function and survival.

Post-ischemic brain neurodegeneration with subsequent neuroinflammation is a major cause of mortality, permanent disability, and the development of Alzheimer's disease type dementia in the absence of appropriate treatment. The inflammatory response begins immediately after ischemia and can persist for many years. Post-ischemic neuroinflammation plays a dual role: initially, it is essential for brain repair and maintenance of homeostasis, but when it becomes uncontrolled, it causes secondary damage and worsens neurological outcome. Neuroinflammation is a complex phenomenon involving interactions between infiltrating immune cells from the peripheral circulation and resident immune cells in ischemic brain areas. This review focuses on the complex relationship between non-coding RNAs, amyloid accumulation, tau protein modifications, and the development of neuroinflammation in the post-ischemic brain. In particular, it clarifies whether the cooperation of non-coding RNAs with amyloid and tau protein enhances neuroinflammation and whether the of neuroinflammatory responses affects the production, behavior, and aggregation of these molecules. Ultimately, elucidating these interactions is critical, as they may contribute to resolving the phenomenon of post-ischemic brain neurodegenerative mechanisms. Furthermore, this review highlights the role of neuroinflammation as a functionally complex immune response regulated/mediated by transcription factors and cytokines. Additionally, it examines how the presence of non-coding RNAs, amyloid aggregation, and modified tau protein may shape the inflammatory landscape. This review aims to advance our understanding of post-ischemic neuroinflammation and its implications for long-term brain health.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor linked to the control of immunological responses. Although AhR has been investigated in relation to lipopolysaccharide (LPS) peripheral inflammation, its role in LPS-induced, astrocyte-mediated inflammation is unknown. This study explores the effect of AhR deletion on astrocyte reactivity and neuroinflammation responses to lipopolysaccharide (LPS). The results show that AhR loss aggravates LPS-induced inflammatory responses using a AhR germline knockout (AhRKO) mouse by increasing pro-inflammatory cytokines levels (TNF-α, IL-1β) and inducible nitric oxide synthase (iNOS) in both primary astrocyte cultures and the mouse hippocampus. Morphologically, astrocytes and microglia from AhRKO mice show increased soma size following LPS injection, suggesting increased glial activation. In addition, AhRKO mice displayed more severe weight loss and locomotor impairment behaviorally following a single systemic LPS injection. Elevated nuclear translocation of NF-κB p65 in AhR-deficient astrocytes provides a potential mechanism for elevated pro-inflammatory signaling. These results emphasize an immunomodulatory role for AhR in reducing astrocyte-driven inflammation and identify AhR as possible therapeutic target for neurodegenerative illnesses linked with neuroinflammatory responses.

Glioblastoma (GBM) progression is linked to aquaporin-4 (AQP4), whose functions extend beyond water transport to influence perivascular architecture, immune modulation, edema, and treatment response. In the healthy brain, AQP4 is highly polarized at astrocytic endfeet, supporting perivascular fluid exchange and glymphatic clearance. In GBM, AQP4 is frequently upregulated and mislocalized, correlating with blood-brain barrier (BBB) disruption, impaired directional fluid movement, and peritumoral edema. Peritumoral astrocytic mislocalization of AQP4, together with tumor mass effect, compromises glymphatic function by distorting perivascular spaces and compressing cerebrospinal fluid (CSF)-Interstitial fluid (ISF) exchange zones. We review evidence that AQP4 isoforms (M1 vs. M23) differentially shape motility and membrane organization, and we outline how AQP4-linked signaling axes (e.g., indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO)-kynurenine-aryl hydrocarbon receptor (AhR) can bias pro-invasive states and immunosuppressive niches enriched with M2-like macrophages). We integrate a four-zone perivascular framework to localize where GBM most perturbs periarterial and perivenous pathways, as well as meningeal lymphatic outflow. Finally, we discuss therapeutic directions spanning AQP4 modulation, isoform balance, and BBB-bypassing delivery strategies. Overall, AQP4 emerges as a mechanistic hub connecting BBB instability, glymphatic impairment, edema, immune evasion, and invasion in GBM.

Fragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. Although structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult knockout mice (), their developmental onset and contribution to early FXS pathophysiology remain unknown.

Serotonin (5-HT) is a neurotransmitter that is involved in retinal development, physiology, and vision, yet the specific contribution of individual 5-HT receptors to retinal function is poorly characterized. We identified 5-HT receptor 1B () as a potential key regulator of serotonergic signaling in the retina.

The anterior retrosplenial cortex (aRSC) functions as a hub that integrates multimodal sensory inputs into associative recognition memories. Although the aRSC receives dense serotonergic projections from the raphe nuclei, the role of serotonin in its function remains poorly understood. Among serotonergic receptors, 5-HT2A receptors (5-HT2ARs) are highly expressed in cortical regions, including the aRSC, and have been implicated in the modulation of cognitive processes. Based on our previous work demonstrating the involvement of the aRSC in recognition memory, here we investigated the contribution of 5-HT2ARs (memory) during different phases of the object recognition (OR) task in rats. We found that selective blockade of 5-HT2ARs in the aRSC differentially affected acquisition, consolidation, and retrieval. These findings identify 5-HT2ARs in the aRSC as critical modulators of recognition memory processing and suggest that their dysregulation could contribute to cognitive impairments observed in conditions such as Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction, motor abnormalities, and memory disorders, with a persistently high and rising incidence. The pathological features of AD include the extracellular deposition of the amyloid beta peptide (Aβ), the accumulation of neurofibrillary tangles (NFTs), and neuroinflammation. Microglia (MG), the main immune cells in the central nervous system (CNS), can transform into different phenotypes. An imbalance in their phenotypic transformation may induce neuroinflammation and lead to neurological diseases, playing a central role in the onset and progression of AD.

Spinal motoneurons are the final output of spinal circuits that engage skeletal muscles to generate motor behaviors. Many motoneurons exhibit bistable behavior, alternating between a quiescent resting state and a self-sustained firing mode, classically attributed to plateau potentials driven by persistent inward currents. This intrinsic property is important for normal movement control, but can become dysregulated, causing motor function deficits, like spasticity. Here we use a conductance-based single-compartment model, together with mouse spinal slice recordings, to investigate the ionic interactions underlying motoneuron bistability. We show that synergistic interactions among high-voltage-activated L-type Ca current ( ), calcium-induced calcium release (CICR) and the Ca-activated non-specific cation current ( ) constitute a minimal mechanistic core that produces plateau potentials and bistable firing. Within this framework, the persistent sodium current ( ) promotes plateau generation, in contrast to the Ca-dependent K current ( ) which opposes it. These results delineate ionic dependencies at the level of interactions rather than spatial localization and provide a tractable basis for interpreting altered motoneuron excitability in disease.

State dependent memory (SDM) occurs when memory retrieval varies with the individual's psychological and physiological state at encoding and recall. Growing evidence shows that internal states shape memory performance across all phases of memory. Examples include affective and physiological conditions, medication effects, and disease states. This review examines how these states affect encoding, storage, and retrieval. We argue that internal states modulate activity in brain regions involved in memory by altering neurotransmitter signaling and by inducing plastic organization of neural circuits and networks. We believe this perspective can guide personalized electrical neuromodulation and multimodal intervention strategies for memory disorders.

Microglia, the innate immune cells of the central nervous system (CNS), play essential roles in maintaining neural homeostasis through dynamic interactions with neurons and other brain structures. While their protective functions are well-established, recent studies have illuminated the detrimental consequences of sustained microglial activation in the context of neurodegeneration. In particular, overactivated microglia contribute to neuroinflammation and induce synaptic alterations through the release of pro-inflammatory cytokines and engagement of specific receptors. These interactions disrupt synaptic structure and function, compromising connectivity, plasticity, and cognitive processes. Notably, neuronal synapses are primary targets of such inflammation-driven dysfunction, where prolonged exposure to cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor- (TNF-α), and signaling via receptor systems including cluster of differentiation-200 (CD200)/CD200 receptor (CD200R), C-X3-C motif chemokine ligand 1 (CX3CL1)/CX3C receptor 1 (CX3CR1), colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R), and interferon- (IFN-γ)/IFN-γ receptor (IFN-γR), lead to impaired learning, excitotoxicity, and neurodegenerative progression. This review synthesizes emerging evidence on the mechanisms by which microglia-mediated immune responses regulate synaptic remodeling, emphasizing the roles of pro-inflammatory cytokines and their receptors in neurodegenerative disorders.

Border-associated macrophages (BAMs) are tissue-resident macrophages in the central nervous system (CNS) that originate from yolk sac progenitors during primitive hematopoiesis. While much is known about their parenchymal counterparts, microglia, recent evidence indicates that BAMs also play roles in neurodevelopment. Located at CNS interfaces such as the meninges, choroid plexus, and perivascular space, BAMs facilitate immune surveillance, vascular modeling, debris clearance, and cerebrospinal fluid dynamics. Despite their strategic location, BAMs have historically been understudied in developmental contexts. This mini review covers their embryonic origins, regional diversification, and functional roles as development progresses. Offering new insights, we consider BAMs in the context of neurodevelopmental disorders (NDDs). Recent findings from maternal immune activation (MIA) studies suggest that fetal BAMs may contribute to aberrant cortical development through altered inflammatory signaling. We propose that, like microglia, BAMs may play previously unappreciated roles in shaping the developmental trajectory of the brain. To aid future research, we also review current tools for studying BAMs and , including new transgenic lines and organoid-based approaches. These tools will be critical for dissecting the molecular functions of BAMs during healthy and disordered development. Understanding BAM biology in early life may reveal novel mechanisms underlying NDDs and inform therapeutic strategies targeting brain-immune interfaces.

Diabetic peripheral neuropathy (DPN), a prevalent and debilitating complication of diabetes, involves complex interactions between peripheral nerve damage and central nervous system (CNS) dysfunction. While traditional research has focused on peripheral and spinal mechanisms, emerging evidence highlights that the brain plays a critical role in the development of painful DPN. This review synthesizes recent advances from neuroimaging, spectroscopy, and preclinical studies to delineate structural, functional, and neurochemical alterations in the central nervous system associated with DPN. Patients exhibit cortical thinning, subcortical atrophy, and disrupted connectivity in sensory, affective, and cognitive networks, accompanied by metabolic imbalances and excitatory-inhibitory neurotransmitter shifts. Preclinical models further implicate maladaptive plasticity, microglial activation, and region-specific astrocytic responses in amplifying central sensitization and pain chronicity. These mechanistic insights underscore the central nervous system as a therapeutic target. Non-invasive neuromodulation techniques, such as repetitive transcranial magnetic stimulation, and brain-directed pharmacological strategies show promising but preliminary benefits in alleviating neuropathic pain. Understanding the interplay between peripheral injury and brain dysfunction in DPN not only broadens the conceptual framework of its pathophysiology but also provides a foundation for developing novel interventions aimed at restoring central network balance and improving patient outcomes.

The external segment of the globus pallidus (GPe) is traditionally viewed as a relay nucleus within the indirect basal ganglia pathway. However, a subpopulation of GPe neurons projects directly to the striatum, raising questions about their compartmental and cell-type-specific targeting.