Dysfunction of the cholinergic system is implicated in the pathophysiology of Multiple System Atrophy (MSA). However, in vivo assessment of cholinergic pathways originating from the nucleus basalis of Meynert (NBM) and pedunculopontine nucleus (PPN), and their clinical relevance remains inadequately characterized.

Acute unilateral peripheral vestibular destruction (AUPVD) causes dizziness, characterized by both visual and motion-related disturbances. Although it is well established that the vestibular nuclei receive auditory and visual sensory inputs and play a critical role in maintaining balance and gaze, the extent to which vestibular activity influences the primary visual cortex (V1) remains unclear. In this study, we observed that V1 neurons failed to generate appropriate responses to motion stimuli using chronic two-photon microscopy in awake AUPVD mice, despite responding normally to static visual inputs. Pharmacological and chemogenetic manipulation of GABAergic signaling in the vestibular nuclei of healthy mice further confirmed that aberrant activity in vestibular inhibitory neurons disrupts V1 neuronal processing. Our findings reveal that the compensatory firing of vestibular inhibitory neurons disrupts normal neuronal responses to motion-related visual stimuli in V1, contributing to dizziness symptoms following peripheral vestibular damage.

The glymphatic system facilitates cerebrospinal fluid (CSF) circulation and metabolic waste clearance in the central nervous system. Its alterations and neuroprotective potentials in cerebral disorders also have been confirmed. However, its role in the optic nerve and involvement in optic neuropathy remain unclear. Here, we utilized the methodology combining fluorescent tracer injection with tissue clearing to visualize and quantify bidirectional glymphatic flow in the optic nerve in mice. Under physiological conditions, low-molecular-weight CSF tracers entered the optic nerve, while intraocular tracers were efficiently cleared via glymphatic pathway-both processes could be temporarily suppressed by using TGN-020. Acute ischemia induced by unilateral common carotid artery occlusion (UCCAO) enhanced CSF accumulation in the optic nerve and impaired intraocular solute clearance. Administration of TGN-020 30 min before ischemia induction reduced CSF accumulation during the ischemic phase and preserved retinal and optic nerve structure and function after ischemia. These findings further reveal a widespread, highly active glymphatic system in the optic nerve. Ischemia-induced dynamic changes of glymphatic function may contribute to optic nerve injury, while usage of TGN-020 during acute ischemia holds certain therapeutic potential in ischemic optic neuropathy.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition marked by recurrent obsessions and compulsions. Over the years, research has primarily focused on the cortico-striato-thalamo-cortical (CSTC) circuit and its neurochemical disruptions as an ideal circuit system for the development of treatment strategies. However, recent findings from neuroimaging studies and rodent research have highlighted the involvement of additional brain regions and network-level dysfunctions that are functionally linked to the CSTC loop. These findings suggest that the sole emphasis on the CSTC circuit is insufficient to address the clinical heterogeneity of the disorder. A broader perspective would therefore better capture the disorder's clinical heterogeneity and diverse cognitive and emotional deficits. Here, we review growing evidence for the role of extra-CSTC brain regions and associated neurotransmitter interactions in OCD, outlining potential pathways for novel therapeutic strategies.

Microglial phagoptosis, defined as the phagocytosis of a viable cell by microglia that ultimately causes the death of the engulfed cell, has emerged as a pivotal process in sculpting neural circuits within the central nervous system (CNS). Essential for neurodevelopmental circuit refinement and ongoing tissue homeostasis, this process relies on dynamic molecular cues that direct microglia to specific cellular substrates. Physiologically, phagoptosis contributes to neural circuit refinement and cell number regulation during development; however, its dysregulation can drive neurodevelopmental and neurodegenerative disorders via aberrant cell removal. Recent advances have elucidated the distinct signaling pathways involved in target recognition and engulfment, revealing the dual roles of microglial phagoptosis in both CNS health and disease. Deeper mechanistic insight into this process offers new therapeutic opportunities for conditions characterized by defective or excessive cell clearance. This review summarizes current progress, highlights unresolved challenges, and discusses future perspectives on targeting microglial phagoptosis for intervention in CNS disorders.

Pain is one of the most prevalent and upsetting symptoms of Parkinson's disease (PD), possibly linked to small fiber neuropathy (SFN). We evaluated small nerve fiber damage in PD patients through corneal confocal microscopy (CCM) and investigated its relationship to pain.

Women during their reproductive years are more susceptible to migraines than men, largely due to the effects of female reproductive hormones. Progesterone receptor (PR) signaling influences episodic migraine susceptibility. Here, we investigated the role of PRs in regulating the transformation from episodic to chronic migraine. Adult female and male C57Bl6 mice, female conditional PR knockout (PRKO) and littermate wild-type (WT) mice, and female mice expressing a Cre recombinase under the progesterone receptor (Pgr) promoter were used. Migraine transformation was induced using five systemic alternate-day nitroglycerin (NTG) injections. Periorbital mechanical thresholds were assessed using von Frey monofilaments. AAV9-mediated transduction was used to express muscarinic acetylcholine receptor-based DREADD complex hM4Di for silencing the activity of PR-expressing somatosensory cortical neurons. Somatosensory cortical neuronal activation was assessed using cFos immunohistochemistry. Gonadally intact female mice were three times more susceptible to developing transformed migraines; they experienced faster pain sensitization after repeated NTG injections compared to males, and their recovery from pain was also slower. PR agonist segesterone promoted migraine transformation in females. In contrast, migraine transformation was slower in PRKO females than in WT females, and their recovery was quicker. PRs are expressed in the somatosensory cortex, and after five NTG injections, there was stronger cFos immunoreactivity in the somatosensory, insular, and cingulate cortices of female WT mice than in PRKO mice. When PR-expressing somatosensory cortical neurons were chemo-genetically silenced, the transition from acute to chronic migraine slowed. PR activation on the somatosensory cortex neurons contributes to the transformation of acute to chronic migraine.

Mutations in Shank3 are the primary genetic cause of Phelan-McDermid Syndrome (PMS), a neurodevelopmental disorder frequently comorbid with autism spectrum disorder (ASD). As a key scaffolding protein in the postsynaptic site, SHANK3 shapes excitatory glutamatergic synaptic function by interacting with AMPARs, NMDARs, and mGluRs. While Shank3 deficiency has been extensively studied in forebrain regions, relatively little is known about its role in the cerebellum, a brain area increasingly implicated in ASD pathobiology and involved in motor and non-motor processing. Since cerebellar granule cells (CGCs) exhibit high Shank3 expression, this study aims to investigate how Shank3 loss affects mossy fiber (MF)-CGC glutamatergic synaptic function. Whole-cell patch clamp electrophysiological recordings from CGCs in ex vivo cerebellar brain slices from adult (4-6 months old) wild type (WT) and homozygous Shank3 KO mice were performed to record miniature, evoked, and photoactivated glutamatergic responses. Immunohistochemistry was used to determine AMPAR subunit (GluA2, GluA4) expression and microglia morphology (IBA1). Quantal mEPSC amplitudes and AMPAR-mediated response to photo-uncaged glutamate were increased in CGCs in the absence of Shank3. Evoked EPSCs recorded in CGCs from Shank3 KO mice had faster AMPAR decay kinetics, inward rectification, and increased sensitivity to IEM-1460, suggesting that a high proportion of CP-AMPARs with distinct biophysical properties are present at the MF-CGC synapse. A reduced density of GluA2 near active zones within cerebellar glomeruli regions containing MF-CGC synapses were consistent with electrophysiological findings. Shank3 KO mice also had less ramified microglia relative to control mice, suggesting a shift in microglial morphology in the cerebellar cortex in early adulthood. Together, these findings highlight a novel role of Shank3 in maintaining the balance between CP- and CI-AMPARs at the MF-CGC synapse, which is essential for synapse maturation and proper cerebellar circuitry function. Dysregulation of this balance, with an altered microglial morphological state in the cerebellum, may be a possible mechanism contributing to cerebellar-related behavioral deficits in Shank3 KO mice and may represent a component of ASD pathophysiology.

Short tandem repeat expansions in C9orf72, DMPK, and CNBP genes cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and myotonic dystrophy types 1 and 2 (DM1/DM2), respectively. Despite distinct clinical phenotypes, these disorders share convergent molecular mechanisms with tissue-specific vulnerability, offering a framework to inform precision therapeutic strategies. Shared pathogenic features include nuclear RNA foci sequestering RNA-binding proteins that disrupt splicing, and repeat-associated non-AUG translation generating toxic dipeptide repeat proteins. In C9orf72, GGGGCC repeats form RNA-driven condensates, including protein-free condensates, via G-quadruplex formation. Evidence also implicates autophagy-lysosome and mitochondrial dysfunction, suggesting a potential "two-hit" loss/gain-of-function model. Clinically, C9orf72 expansions primarily affect motor neurons and frontotemporal circuits, with ALS progression typically occurring over 2-5 years. Conversely, myotonic dystrophy manifests as a muscle-predominant multisystem disorder progressing over decades. Genomic instability contributes to disease variability, with anticipation and parent-of-origin effects strongest in DM1, not confirmed in DM2 and controversial in C9orf72. Sequence interruptions modulate repeat stability and phenotype, influencing diagnostic interpretation. Therapeutic development has yielded contrasting outcomes. Antisense oligonucleotides targeting C9orf72 achieved target engagement and reduced dipeptide repeat proteins but failed clinically, potentially due to sense-strand selectivity and persistence of TDP-43 pathology. In contrast, RNA-targeting conjugates for DM1 (delpacibart etedesiran and DYNE-101) received FDA Breakthrough Therapy designation. Therapeutic success depends on tissue accessibility and addressing both shared and circuit-specific pathogenic cascades. While nuclear RNA targets appear druggable in myotonic dystrophy, the bidirectional transcription and compartmentalized pathology of C9orf72 ALS/FTD may require multi-targeted approaches for precision medicine.

KIF5C, a kinesin-1 motor protein critical for neuronal cargo transport, has been clinically associated with developmental delay and intellectual disability (DD/ID), although its pathogenic mechanisms are yet to be elucidated. Building on our prior identification of a de novo heterozygous KIF5C variant in a patient with DD/ID, a conditional knock-in mouse model was constructed to determine disease pathogenesis. The mutant mice exhibited core clinical phenotypes, including growth retardation, microcephaly, and deficits in social and spatial memory. Electrophysiological recordings revealed a decreased frequency of miniature excitatory postsynaptic currents, impaired long-term potentiation, and altered presynaptic vesicle release probability. Mechanistically, hippocampal neurons displayed decreased mature dendritic spines and impaired axonal mitochondrial transport, collectively contributing to diminished excitatory neurotransmission. Nonetheless, the overexpression of KIF5C in hippocampal CA1 neurons enhanced memory performance and excitatory synaptic transmission in the mutant mice. Overall, these findings establish that KIF5C dysfunction disrupts dendritic spine maturation at the postsynaptic terminal, axonal mitochondrial transport, and presynaptic vesicle release. Thus, a critical cellular mechanism underlying DD/ID pathogenesis has been identified in this research, opening novel therapeutic avenues.

Krabbe disease (KD) can be classified into early-infantile, late-infantile, juvenile, and adult form subtypes. Adult form KD is relatively rare and lacks systematic characterization of clinical, imaging, and lipidomic features. This cross-sectional study aimed to define characteristic white matter hyperintensities and plasma lipidomic profiles to identify potential correlations with clinical severity.

Mouse double minute 2 homolog (MDM2) is a key negative regulator of the p53 pathway, functioning through its E3 ubiquitin ligase activity to control cell-cycle progression, DNA damage response, and apoptosis. Recent findings reveal that MDM2 also plays multifaceted roles in the central nervous system (CNS), extending beyond its canonical oncogenic functions. Increasingly, MDM2 has been implicated in the pathogenesis and progression of neurodegenerative diseases, brain injury, neuroinflammation, and cognitive dysfunction.This review integrates current advances on the non-canonical roles of MDM2 in CNS disorders, focusing on its involvement in mitochondrial homeostasis, autophagy regulation, synaptic plasticity, immune modulation, and metabolic signaling. Unlike previous reviews that addressed MDM2 mainly in oncogenesis or single neurological conditions, this work establishes a stage- and cell-type-specific framework of MDM2 regulation within the CNS. It distinguishes p53-dependent stress-surveillance mechanisms from p53-independent repair and metabolic pathways and introduces a therapeutic-window concept that balances neuroprotection with adaptive stress responses.Together, these perspectives position MDM2 as a dynamic molecular switch orchestrating neuronal fate, providing conceptual foundations for context-specific therapeutic strategies in neurological disease.

The endocannabinoid (eCB) system modulates many biological processes, including adult neurogenesis, emotional behaviour and stress-related signaling pathways. Intrinsic levels of eCB ligands, such as anandamide, are regulated in part, by fatty acid binding protein 5 (FABP5), a chaperone protein that transports anandamide for hydrolysis. Here, using preclinical rodent models, we examined the effects of pharmacological FABP5 inhibition on anxiety- and depressive-like behaviours and associated molecular signaling pathways, following exposure to chronic stress. In addition, we investigated the impacts of chronic stress on hippocampal neurogenesis and how FABP5 inhibition may modulate stress-induced deficits in hippocampal neurogenic mechanisms. Remarkably, we report that anxiety- and depressive-like behaviours are strongly prevented by systemic FABP5 inhibition and associated with altered transcription of IGF-1, CB and GPR receptors as well as by altered phosphorylation of Erk1/2, Akt and p70S6 kinase pathways in the limbic circuitry. Finally, FABP5 inhibition potently blocked stress-induced reductions in hippocampal neurogenesis, identifying FABP5 inhibition as a promising pharmacotherapeutic candidate for stress-induced mood and anxiety symptoms.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2-R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2 mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2 mice also presented with signs of milk aspiration and lung pathology. Interestingly, P0 Ighmbp2 mice had visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the pathology of the sciatic nerve, hindlimb neuromuscular junction and muscle. Injection of the ssAAV9-WT-IGHMBP2 vector extended Ighmbp2 survival a few days. Ighmbp2 phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.

Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder associated with autism spectrum disorder and intellectual disability, is caused by either deletions in human chromosome 22q13 or mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. PMS is highly debilitating, and existing treatments are ineffective. SHANK3 interacts with at least 3 synaptic receptors through synaptic-associated proteins, some of which are upstream of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathways. Metformin, an inhibitor of the mTORC1 and MAPK/ERK signalling pathways, was shown to correct core phenotypes in a fragile X mouse model, offering therapeutic potential for PMS. Male Shank3B, a PMS mouse model, and wild-type mice were treated from birth with metformin (5 mg/mL) or vehicle. Shank3B mice displayed increased self-grooming, decreased social interaction, reduced duration and frequency of ultrasonic vocalisations, and impaired hippocampal-dependent memory. Upregulated mTORC1 activity was observed in the hippocampus and prefrontal cortex, along with decreased synaptosomal protein expression in the striatum of GluN2B (an N-methyl-d-aspartate receptor (NMDAR) subunit), Homer1 (a synaptic-associated protein) and GluA2 (an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit), all of which interact with Shank3. Metformin treatment from birth corrected core behavioural impairments, exaggerated mRNA translation, and decreased striatal synaptic protein expression. Considering its exceptional safety profile, metformin is a promising therapeutic option for a rapid clinical translation of PMS treatment.

Multiple system atrophy (MSA) is a progressive and fatal α-synucleinopathy characterized by α-synuclein-positive (α-syn) glial cytoplasmic inclusions in oligodendrocytes. The cerebellar variant (MSA-C) primarily affects olivopontocerebellar fibers, resulting in extensive demyelination and glial activation. To model this pathology, we developed a Tet-Off-based MSA-C mouse model with oligodendrocyte-specific overexpression of human A53T α-syn. Upon doxycycline withdrawal at 8 weeks of age, mice developed progressive cerebellar ataxia by 26 weeks and succumbed by 30 weeks. These mice exhibited severe demyelination and marked activation of microglia and astroglia in the brainstem and cerebellum, along with widespread propagation of α-syn oligomers and phosphorylated α-syn (p-α-syn) aggregates in oligodendrocytes, astrocytes, and neurons. Single-cell RNA sequencing of CD11b cells from the brain and spinal cord identified a distinct microglial cluster expressing Toll-like receptor 2 (Tlr2), transglutaminase 2 (Tgm2), arginase-1, macrophage scavenger receptor-1 (Msr1), inflammatory genes (such as Nfkbia, Nfkbiz, and Il1b), and chemokines (including Ccl3, Ccl4, and Ccl12). These microglia were located adjacent to p-α-syn aggregates and were distinct from previously described protective disease-associated microglia and border-associated macrophages. TLR2- and TGM2Iba1 microglia were particularly enriched in demyelinating lesions. Prophylactic administration of the CSF1R inhibitor BLZ945 exacerbated motor deficits and demyelination, significantly increasing this microglial population. Similarly, MSR1 and CD68 microglia/macrophages were observed in early pontocerebellar lesions of six human MSA-C autopsy cases. These findings suggest that this pro-inflammatory microglia subset plays a central role in disease progression and may represent a promising therapeutic target for modifying the course of MSA-C and related synucleinopathies.

The hippocampus plays a crucial role in memory and emotional regulation, with its dorsal pole supporting cognitive functions and the ventral hippocampus modulating anxiety and affective processing via limbic interactions. Chronic restraint stress induces anxious- and depressive-like behaviors in rodents, alongside transcriptomic changes in the ventral hippocampus. Emerging evidence highlights microRNAs as modulators of synaptic architecture and gene expression. Notably, miR-17-5p-part of the miR-17-92 cluster- shows increased cortical expression in individuals with mood disorders, and its levels in neural extracellular vesicles correlate directly with depressive symptom severity in male patients, suggesting translational relevance. In rodent models, chronic stress exposure produces divergent hippocampal expression patterns of miR-17-5p. Whether miR-17-5p acts as a passive biomarker of mood disorder or actively contributes to stress adaptation remains unclear. In the present study, chronic stress exposure increased miR-17-5p expression specifically in the ventral hippocampus of male rats, with no changes detected in females. To assess its functional relevance, we reproduced this alteration in the ventral hippocampus of naïve male to evaluate behavioral outcomes and characterize both global and synaptic transcriptomic and proteomic profiles. Behaviorally, miR-17-5p mimic administration increased the sucrose preference, revealing an antidepressant-like effect. On the other hand, the open field test did not reveal anxiety-related differences, whereas the novelty-suppressed feeding test indicated a decrease in anxious-like behavior following miR-17-5p administration. Molecular analyses in ventral hippocampus homogenates and synaptic-enriched fractions revealed modulation of ribosomal protein composition and translational regulation-likely through mTOR pathway activation-favoring GABAergic adaptation and synaptic remodeling. These findings suggest a region-specific role of miR-17-5p in the ventral hippocampus that may contribute to its anxiolytic and antidepressant-like effects. These results provide novel insights into miR-17-5p-mediated mood regulation, highlighting its potential as a therapeutic target for anxiety and depressive disorders.

c-Jun N-terminal kinases (JNKs) are implicated in both neurodegeneration and mood regulation, including anxiety and depressive-like behaviours. Yet the consequences of JNK inhibition in vivo on protein phosphorylation in the brain remain largely unknown. This study aimed to (1) determine how chronic JNK inhibition altered proteome-wide phosphorylation in hippocampus and nucleus accumbens, regions central to affective processing, and (2) determine which JNK-regulated phosphoproteins were associated with the anxiolytic response, representing potential drivers. Mice underwent intracerebral (ICV) infusion with DJNKI-1 or control TAT peptide for six weeks, after which behaviours were assessed and phosphoproteomic profiling performed. JNK inhibition reduced anxiety-like behaviour and significantly altered 163 and 97 phosphosites in the hippocampus and nucleus accumbens, respectively. JNK-regulated phosphoproteins were enriched for regulators of cytoskeleton organization and synaptic function. GSK3 signalling was inhibited by DJNKI-1, leading to extensive depletion of phosphorylation on GSK3 motifs within the hippocampus and nucleus accumbens. These affected proteins involved in adhesion, cytoskeleton, proteostasis and synaptic activity. Moreover, several energy metabolism proteins exhibited phosphorylation changes on sites that control their enzymatic activity. The predicted net effect is a metabolic shift from oxidative phosphorylation to anaerobic glycolysis. Network analysis revealed enhanced phosphoproteome connectivity in mice displaying low anxiety-like behaviour, with spectrin-α/β, syntaxin-1b, CRMP2 and MAPT emerging as central hubs. Notably, claudin-11, an oligodendrocyte-specific, tight junction protein, was identified as a novel phospho-target that was highly reduced upon DJNKI-1 treatment. Together, these findings highlight potential molecular markers of anxiolytic response and suggest synaptic and metabolic interplay in mood regulation.

Zinc finger E-box-binding homeobox 2 (ZEB2) is a key transcription factor involved in multiple aspects of nervous system development, including neuronal specification, migration, and differentiation. Loss-of-function variants in ZEB2 cause Mowat-Wilson syndrome (MWS), a severe neurodevelopmental disorder characterized by intellectual disability, epilepsy, and brain structural abnormalities. In this study, we generated and characterized induced pluripotent stem cell (iPSC) lines from MWS patients carrying pathogenic ZEB2 variants. Patient-derived iPSCs retained full pluripotency and were capable of differentiating into all three germ layers, including neural lineages. Upon directed differentiation into neural progenitor cells (NPCs) and early neurons, we identified distinctive transcriptional alterations affecting neuroepithelial-to-radial glia transition and lineage specification. RNA-seq analysis revealed dysregulation of genes involved in cytoskeletal remodeling, extracellular matrix organization, and cell motility. Functional holographic live imaging confirmed a significant increase in motility behavior in MWS NPCs and early neurons, suggesting that altered cell dynamics may underlie aberrant neural circuit formation. Despite these changes, early neuronal markers such as MAP2 were expressed at comparable levels in MWS and control cells. Together, these findings uncover novel cellular and molecular phenotypes associated with ZEB2 deficiency and provide insight into how disrupted progenitor behavior and transcriptional mis-regulation may contribute to the neurodevelopmental features of MWS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative non-cell-autonomous disease with no cure, thus research is intensely focused on identifying pharmacological targets. Several studies aimed to clarify the pathogenic mechanisms and involvement in various cell types. A crucial factor in ALS is autophagy, which plays a key role in degrading intracellular protein aggregates. The connection between ALS and autophagy is reinforced by the fact that several genes mutated in ALS are linked to fundamental aspects of autophagy. The blockage of the autophagic flux was observed in ALS motor neurons, where it occurs earlier than in glia. However, the inconsistent effects of autophagy modulators in preclinical and clinical studies indicate the need for a deeper understanding of the role of autophagy in other cell types, such as astrocytes, microglia, and oligodendrocytes. Astrocytes and microglia are significantly impacted by autophagy dysregulation, contributing to neurodegeneration in both mouse and human-derived models. Autophagy is overactivated early in the disease, even before symptoms appear. This overactivation is influenced by the timing and specific tissue involved. It can alter cells' immunophenotype, favouring proinflammatory responses and affecting the cellular environment and autophagy in the surrounding cells. In contrast, oligodendrocytes show mild autophagic alterations. Additionally, sex hormones may affect proper autophagy function and ALS progression. The lack of information on how sex influences autophagy in glia highlights the need for more nuanced investigation into this mechanism. Future research should focus on these aspects, paving the way for personalised pharmacological approaches that consider the roles of cell types, time of intervention, and sex.