Appropriate histone modifications are essential for maintaining functional chromatin structure and gene expression, and dysfunction of their regulators has been linked to a variety of diseases. Among these modifications, trimethylation of lysine 4 on histone H3 (H3K4me3) is a well-characterized epigenetic mark enriched at transcription start sites of actively transcribed genes. H3K4me3 regulates gene transcription by recruiting transcription factors, facilitating chromatin accessibility, and preventing DNA methylation. In mammals, methylation of H3K4 is catalyzed by a family of histone methyltransferases including SET domain containing 1A (SETD1A), which is primarily responsible for genome-wide deposition of H3K4me2/3. Loss-of-function variants in SETD1A, highlighting its critical role in brain development and cognitive function, are strongly associated with schizophrenia (SCZ) and other neurodevelopmental disorders, but the underlying mechanisms remain largely unclear. To better understand the epigenetic and neurobiological consequences of SETD1A dysfunction, non-human primate models can serve as a useful tool because of their close evolutionary relationship to humans and highly developed cognitive abilities. In this study, we established a genetically engineered common marmoset (Callithrix jacchus) lineage carrying a frameshift mutation in SETD1A, which is, to the best of our knowledge, the first non-human primate lineage carrying a mutation in an epigenetic regulatory gene associated with SCZ, and confirmed germline transmission of the mutant allele. In a comparison between fibroblasts derived from one SETD1A mutant and one wild-type marmoset, the mutant showed a lower SETD1A protein level, modest differences in H3K4me3 deposition, and broader differences in gene expression profiles. Although these molecular observations require validation using additional biological replicates, the establishment of this SETD1A mutant marmoset lineage provides a valuable platform for bridging molecular mechanisms with primate neurobiology and for investigating the role of epigenetic regulation in the pathophysiology of neuropsychiatric and neurodevelopmental disorders.
Recently, Japan conditionally approved the first cell transplantation therapy for a central nervous system disorder using induced pluripotent stem cells as the source of dopaminergic progenitors to treat Parkinson's disease. This milestone was achieved almost 40 years after the first cell therapy trial for Parkinson's disease in Lund, Sweden, and 18 years after the first clinical trial using oligodendrocyte progenitors derived from pluripotent stem cells for spinal cord injury. In this review, we update the current state of development of cell therapies based on pluripotent stem cells for diseases of the central nervous system and discuss the potential effects of neuroinflammation on these cell therapies. Focusing on Parkinson's disease, we summarize data showing the functional relevance of tumor necrosis factor-alpha for the differentiation and viability of pluripotent stem cell-derived dopaminergic progenitors and its dual effects on endogenous dopaminergic neurons, as presented at the Second Meeting of the Latin American Glia Club, held April 7-9, 2025, in Buenos Aires, Argentina. In addition, we propose areas of cell transplantation in Parkinson's disease in which research efforts could be focused and present a cautionary note on the use of non-selective anti-tumor necrosis factor-α therapies alongside pluripotent stem cell-derived dopaminergic progenitor transplantation. Finally, we provide an in-depth list of TNF receptor agonists and antagonists and specific TNF-mediated cell-death inhibitors and discuss their properties as possible candidates for increasing dopaminergic progenitor survival after transplantation in patients with Parkinson's disease.
It has now been well established that gut microbiota significantly influences emotional and neuroendocrine responses to stress. Specifically, multiple pieces of evidence from various preclinical models indicate that gut microbiota regulates the response of the hypothalamic-pituitary-adrenocortical (HPA) axis to acute and chronic stress. In contrast, the influence of gut microbiota on the adrenomedullary tissue, which is responsible for the production and release of catecholamines-the first hormones released in response to stress-has received little attention. Therefore, our study aimed to explore whether adrenal corticosterone and catecholamine biosynthesis were differently regulated in germ-free (GF) and conventional, specific pathogen-free (SPF) male rats when exposed to unpredictable chronic mild stress, acute metabolic stress, or both. Results showed that both GF and SPF chronically stressed rats had significantly (p < 0.05) heavier adrenal glands (+30% for GF, +21% for SPF) compared to unstressed animals. Gene expression levels of corticosterone biosynthesis enzymes and plasma and adrenal corticosterone concentrations did not differ significantly between control rats and those exposed to chronic, acute, or both stress factors, whether in GF or SPF rats. The same result was observed for the genes encoding tyrosine hydroxylase and dopamine β-hydroxylase, two enzymes involved in catecholamine biosynthesis. By contrast, GF rats exhibited a 2.3-fold increase (p = 0.0271) in Pnmt gene expression (which encodes phenylethanolamine N-methyltransferase, the enzyme responsible for converting norepinephrine to epinephrine) and a 2.6-fold increase (p = 0.0786) in epinephrine concentration in the adrenal glands under combined stress conditions. This response was not observed in SPF rats. In these animals, chronic stress was found to reshape the composition and metabolic functions of the gut microbiota. Interestingly, this was accompanied by a 40% decrease in norepinephrine (p = 0.0364) and epinephrine (p = 0.0840) concentrations in their adrenal glands. This study highlights the gut microbiota as a regulator of adrenomedullary activity, enhancing our understanding of the interaction between peripheral and central stress circuitry.
The loss of ovarian hormones in postmenopause influences cognition, emotion and energy homeostasis, processes integrated by the hippocampus. The mechanisms by which estradiol influences this area have not been fully understood. The present study aimed at investigating the effects of estradiol on the rat hippocampus proteome of ovariectomy-induced menopause either followed by estradiol replacement or not. Eighteen 3-month-old female Wistar rats were either ovariectomized or sham operated and fed with standard chow for 3 months. A subgroup of ovariectomized rats received estradiol replacement. The hippocampi were processed using data independent acquisition MS-based proteomics and differentially expressed proteins were submitted to bioinformatics analysis for a pathway-based functional understanding of the estradiol effects. Proteomic analysis revealed that 49 hippocampal proteins were modulated by ovariectomy and estradiol replacement. Functional analysis of the differentially expressed proteins revealed the enrichment of terms related to energy metabolism (comprising glycolysis/gluconeogenesis, pyruvate metabolism, oxidative phosphorylation, and response to oxidative stress) and neuron projection (comprising cytoskeleton organization, regulation of vesicle-mediated transport, and modulation of chemical synaptic transmission). The present dataset indicates that, at the hippocampus, estradiol affects mitochondrial dynamics, lipid metabolism and intracellular trafficking machinery and influences dendritic and synaptic transmission and brain plasticity. Some alterations observed in proteins have not yet been described in the hippocampus in the context of menopause and estradiol replacement. These data provide new insights into the mechanisms involved with menopause effects and may help future studies related to drug development for the prevention and treatment of postmenopause associated symptoms.
Catecholamines such as dopamine (DA) and norepinephrine (NE) are critical neuromodulators which influence a wide range of physiological and behavioral processes. Optical sensors/probes are powerful tools to detect catecholamines with high spatial and temporal resolution, enabling real-time imaging in complex biological environments. In this review, we highlight recent advances in single-walled carbon nanotube (SWCNT) sensors and genetically encoded sensors for fluorescence-based catecholamine detection. We illustrate how these technologies have enabled new biological discoveries by allowing the spatiotemporal mapping of catecholamine release dynamics with unprecedented resolution. We discuss the complementary features of these techniques and remaining key challenges including molecular selectivity, tailored kinetics, and enhanced tissue penetration. Finally, we outline future directions and opportunities for integrating these technologies into neuroscience research, aiming to expand our understanding of catecholaminergic signaling across scales.
Spinal cord injury (SCI) triggers an immediate and sustained disruption of the composition and organization of the neuronal cytoskeleton. Radical alterations in axonal and dendritic microtubules characterize both the acute injury phase and the protracted recovery period. For decades, researchers have sought to correct these microtubule defects as a therapeutic strategy to encourage axonal regeneration, collateral sprouting, and the functional rewiring of neuronal circuits. Recent studies have demonstrated that taxol and related microtubule-active drugs improve outcomes in rodent models. These benefits are achieved by preventing microtubule depolymerization, stabilizing existing polymers, and promoting new assembly within both afflicted neurons and the glial cells essential for repair. While these findings highlight the therapeutic potential of microtubule-based interventions, we posit that successful clinical translation necessitates a more sophisticated approach rooted in the growing knowledge of microtubule-related proteins and their intricate regulatory mechanisms. This review evaluates progress in this arena, specifically examining the microtubule interactome network that includes structural microtubule-associated proteins (MAPs) such as Tau, MAP1A, MAP1B, MAP2, and MAP6, as well as the stathmin family, plus-end tracking proteins, and microtubule-severing proteins such as fidgetin and spastin. In addition, we analyze the contribution of molecular motor proteins and regulatory MAPs, including CRMP2 and CRMP4, as well as upstream transcription factors governing their expression. Finally, we address convergent regulation through kinases such as GSK3β and CDK5, which represent a central mechanistic axis linking injury signaling to cytoskeletal failure. By integrating data from studies on development and regeneration into a unified mechanistic model, we provide a framework for microtubule-based therapeutics for SCI.
Methylglyoxal is a highly reactive by-product of glycolysis that is elevated in diabetes and contributes to the development of diabetic peripheral neuropathy (DPN). DPN is characterized by nerve degeneration, typically manifesting in patients' extremities. This leads to patients experiencing numbness, burning, and pain. It has been established that elevated methylglyoxal levels lead to nociception, but the broader cellular effects of methylglyoxal on neurons in the dorsal root ganglia (DRG) remain poorly understood. This review provides mechanistic insight regarding methylglyoxal's impact on various cell types and disease contexts. Five main mechanisms were identified: protein glycation, proteostasis change, oxidative stress, metabolic changes, and increased inflammation. These mechanisms are thoroughly interconnected, contributing to cellular dysfunction associated with DPN. We propose that methylglyoxal functions as a central mediator in cellular stress, linking hyperglycemia and elevated glycolysis to neuronal dysfunction in DPN. There is extensive evidence that these mechanisms are methylglyoxal-driven in other cell types and diseases, but a gap in the field remains in determining whether and how they occur in DRG neurons. This is particularly important, as DPN is a frequent comorbidity in diabetes and metabolic diseases and greatly affects patients' quality of life. Understanding the effect of methylglyoxal on DRG in relation to these mechanisms will provide novel insights into the development of DPN and lead to new therapeutic targets.
ABSTRACT Sphingosine‐1‐phosphate receptors (S1PRs) play an important regulatory role in various biological processes, including immune responses and neurodegeneration. We report the binding specificity of an S1PR1 PET radiotracer, [ 18 F]TZ82112, via in vitro autoradiography blocking studies with S1PR1 modulators in human and rat brain tissues and evaluate the tracer kinetics via kinetic modeling in nonhuman primates (NHPs) to assess its potential for clinical translation. A total of 12 scans were performed in four male macaques (M 1–4). Each macaque had 1–4 baseline scans and at least one blocking scan in three macaques. Arterial input function (AIF) was obtained from M2 and M3 under baseline conditions and M3 after pretreatment with cold TZ82112. The metabolite‐corrected plasma AIF was applied to several kinetic models—one‐tissue compartment (1TC) and 2TC, and Graphical Logan Analysis. Five candidate reference regions, namely the whole cerebellum, brain stem, occipital cortex, corpus callosum, and cerebral white matter, were investigated for deriving the standardized uptake value ratios ( SUVr ). The 2TC with four parameters (2TC4K) with blood volume ( V b ) fitting is the most suitable kinetic model for evaluating [ 18 F]TZ82112 kinetics. Pretreatment with unlabeled TZ82112 reduced uptake of [ 18 F]TZ82112, demonstrating specific binding in all analyzed regions, including potential reference regions. Reduced tracer uptake in in vitro blocking studies further confirmed the tracer specificity to S1PR1. We concluded that accurate [ 18 F]TZ82112 quantification requires AIF measurements, owing to the lack of a suitable reference region; no reference region modeling approach or SUVr would be appropriate. Fast tracer uptake and high V T values, particularly in the prefrontal cortex and striatum, indicated that [ 18 F]TZ82112 enters the brain quickly and has high S1PR1‐specific binding in NHP brain. The current findings further support [ 18 F]TZ82112 as a good PET radiotracer for the quantification of S1PR1 in the brain, provided an AIF is employed. image
The SH-SY5Y human neuroblastoma cell line is widely used as an in vitro model of β-amyloid (Aβ) neurotoxicity in Alzheimer's disease (AD). However, the lack of standardized protocols for assessing Aβ toxicity-including differentiation strategies for SH-SY5Y cells-limits the comparability of results across studies. To address these issues, we conducted a systematic review and meta-analysis to evaluate how methodological factors influence Aβ-induced toxicity in SH-SY5Y cells. We included 359 eligible studies encompassing 1192 MTT-based comparisons of cell viability between Aβ-treated and control SH-SY5Y cells. A three-level meta-analysis estimated mean cell viability after Aβ exposure at 63% of control levels (95% CI [61.6; 64.3]), with very high heterogeneity (I2 = 99.6%). Meta-regression identified significant associations between increased toxicity and higher Aβ concentrations, longer exposure durations, and the use of peptide preparations described as fibrils. Conversely, differentiation protocols, duration, and cell density did not significantly influence toxicity outcomes. Reporting quality was often poor, with frequent omissions regarding cell line origin, authentication, contamination testing, Aβ preparation details, and nature of the experimental unit. Overall, our findings show robust Aβ toxicity in SH-SY5Y cells, primarily driven by dose, exposure time, and Aβ aggregation state, but not cell differentiation status. Our conclusions highlight the critical need for better reporting of Aβ exposure parameters to enhance reproducibility and translational potential in AD research.
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary pathology, synaptic dysfunction, and chronic neuroinflammation, yet the mechanisms driving early, localized pathology remain elusive. While traditionally viewed through a neuron-centric lens, astrocytes express abundant amyloid precursor protein (APP)-predominantly Kunitz-type protease inhibitor (KPI)-containing isoforms-and possess the complete enzymatic machinery for APP processing and Aβ clearance. Astrocytic APP is a stress-responsive signaling molecule regulated by inflammatory, metabolic, excitotoxic, and mechanical insults. Under local tissue stress, reactive astrocytes upregulate APP and shift toward amyloidogenic processing. The resulting bioactive fragments, including Aβ, promote astrocyte activation, disrupt homeostatic functions, and trigger feed-forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self-reinforcing network where APP integrates local stress and diffusible Aβ propagates reactive states across the astroglial syncytium. This framework positions astrocytic APP signaling as an upstream driver of localized amyloid accumulation, neuroinflammation, and sporadic AD progression.
Nanosecond electric pulses (NEP) are being explored as a novel bioelectric stimulus to modulate neurosecretion. Recently we reported that NEP trigger transient, voltage-gated Ca2+ channel-mediated Ca2+ influx in cultured murine adrenal chromaffin cells (ACC) expressing the genetically-encoded Ca2+ indicator GCaMP6f. The present study investigated ACC Ca2+ responses to NEP in acute adrenal slices from mice that expressed GCaMP6f in both ACC and satellite glial cells (SGC), as well as exclusively in SGC. Adrenal glands from male and female mice were sectioned into 100 μm slices that were placed in a chamber and perfused at a rate of 3-4 mL/min with a balanced salt solution maintained at 35°C. A custom-fabricated non-contact electrode delivered NEP ranging from 12 to 90 ns to a large area of the adrenal medulla. Our results show that a single 30 ns pulse elicited a rapid, transient rise in intracellular Ca2+ in ACC in situ. Like NEP-induced Ca2+ responses in cultured ACC, ACC Ca2+ responses in situ depended on extracellular Ca2+ and voltage-gated Ca2+ channel activation. The nicotinic receptor antagonist hexamethonium failed to inhibit these responses, indicating that NEP stimulation, in contrast to stimulation with conventional duration electrical pulses, activates ACC directly rather than indirectly through activation of splanchnic nerve terminals. Furthermore, NEP exposure of the adrenal medulla also resulted in Ca2+ increases in surrounding SGC that were slower in onset and longer in duration than those evoked by NEP in ACC. Finally, comparison of Ca2+ responses elicited by NEP trains in ACC in situ to those evoked by such trains in ACC in vitro revealed that the native tissue environment promotes more highly synchronized Ca2+ responses. Together, these results lay the foundation for future studies exploring the potential for NEP to modulate catecholamine release from ACC remotely and non-invasively in vivo.
The evolution of the human brain underlies our higher-order cognitive functions. In particular, the cerebral cortex, the outermost layer of the brain, has rapidly evolved to contain a disproportionately large number of neurons relative to the rest of the brain. Much of this expansion is attributed to the enlargement and diversification of the pool of neural precursors, which proliferate and differentiate into the neurons and glia of the brain. How the human cerebral cortex has evolved remains an active area of investigation. With the advent of pluripotent stem cell and brain organoid technologies, comparative genomic studies between humans, mice, and nonhuman primates have identified human-specific genes or pathways during neurodevelopment. The utility of these models relies on the ability of brain organoids to preserve the cytoarchitecture and species-specific developmental trajectories of diverse neural and glial cell types that are observed in vivo. This review will discuss how brain organoids recapitulate aspects of interspecies differences during cortical development, specifically neural precursor expansion, neurogenesis, and gliogenesis, and how these models can be improved to enable a deeper understanding of human brain evolution. Unraveling the cellular and molecular mechanisms underlying cross-species differences in brain expansion could also provide key insights into neurodevelopmental diseases, particularly those where brain size is affected.
Astrocytes are among the first cellular responders to central nervous system injury, yet the mechanisms governing their earliest responses remain incompletely understood. Here, we investigated astrocyte dynamics during the first hours after focal cortical injury induced by cortical devascularization in rats. We observed a rapid and spatially restricted increase in glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) immunoreactivity surrounding the ischemic core as early as 1.5-3.5 h post-lesion, in association with blood-brain barrier disruption and edema-related changes. Within the injury core, astrocytes displayed differential GFAP detection by monoclonal and polyclonal antibodies, together with the appearance of lower-molecular-weight GFAP fragments both in vivo and after oxygen-glucose deprivation in vitro, suggesting GFAP cleavage in severely damaged astrocytes. At the chromatin level, astrocytes proximal to the lesion exhibited reduced histone H3 acetylation, particularly histone 3 acetylation at lysine 9 (H3K9ac), a phenomenon recapitulated in cultured astrocytes exposed to hypo-osmolar stress. This reduction was transient, reversible upon recovery, and prevented by histone deacetylase (HDAC) inhibition. Functionally, hypo-osmolar stress conditioned astrocyte responses to subsequent stimuli, attenuating nuclear factor kappa B (NF-κB) activation and complement 3 (C3) induction after lipopolysaccharide exposure while enhancing proliferative capacity during recovery. Together, these findings identify edema-associated osmotic stress as an early regulator of astrocyte epigenetic state and functional plasticity, suggesting that astrocytes exposed to edema are primed to adopt distinct responses that may contribute to tissue repair and scar formation following brain injury.
The mammalian target of rapamycin (mTOR) is a key regulator of neuronal development, metabolism, and plasticity, and its dysregulation is linked to many neurological disorders. Most studies have focused on cytoplasmic mTOR, yet mTOR is also present in the nucleus. In non-neuronal cells, nuclear mTOR has been linked to transcription, chromatin organization, and RNA metabolism. In neurons, its role remains largely unknown. Here, we present a focused Perspective on nuclear mTOR in the nervous system. We briefly summarize the best-established nuclear functions of mTOR, drawing mainly on evidence from non-neuronal cells. We then reanalyze published mTOR interactome datasets to assess whether these mechanisms may be relevant to neurons. Repeated links were observed to nuclear processes, particularly transcription, chromatin regulation, RNA processing, and DNA repair. Similar patterns were observed for gene sets associated with neurodevelopmental and neurodegenerative disorders. However, these associations are correlative and do not establish causality. Based on these findings, we propose a set of testable predictions and experimental approaches to directly examine nuclear mTOR function in neurons, including selective perturbation of its nuclear activity and analysis of gene expression and RNA processing. A key open question is whether nuclear mTOR has a functional role in neurons beyond its well-established cytoplasmic activities. This Perspective summarizes current evidence, highlights key gaps, and outlines directions for future studies on nuclear mTOR in neuronal function and disease.
Adult neurogenesis in the dentate gyrus (DG) of the hippocampus is a dynamic and tightly regulated process that is finely regulated by a diverse array of transcription factors. While the transcription factor Etv5, a member of the Erythroblast Transformation Specific (ETS) family, has been implicated in embryonic development by regulating cell proliferation and differentiation across various tissues, its specific role in adult hippocampal neurogenesis remains unexplored. Here, we show that conditional ablation of Etv5 specifically in adult-born granule cells (GCs) increases the proportion of Doublecortin (DCX)-positive immature GCs at the expense of mature neurons, without affecting the proportion of neither radial glia-like cells (RGCs) nor SOX2+ progenitor cells within the neurogenic niche. Furthermore, Etv5 conditional mutant mice exhibit reduced dendritic complexity and defects in spine development, indicating impaired neuronal maturation and suggesting deficits in synaptic integration of adult-born GC neurons.
A key question in neuroscience is how memories are formed and maintained at the molecular and cellular levels. Key findings on the importance of transcriptional and translational changes after an experience has occurred have not yet been transformed into a mechanistic understanding of how neuronal and synaptic properties encode the experience. In this special issue of the "Molecular and Cellular Mechanisms of Memory" we bring together 8 manuscripts that address this issue from a broad range of perspectives.
Alzheimer's disease (AD) is the leading cause of dementia, characterized by irreversible neuronal loss and progressive cognitive decline. The disease is driven by complex and interconnected pathological processes, including amyloid-β plaque deposition and tau neurofibrillary tangle formation, which converge on neuroinflammation, oxidative stress, synaptic dysfunction, and widespread neuronal network failure. Although recently approved antibody-based therapies such as lecanemab and donanemab effectively reduce cerebral amyloid burden, their clinical benefits remain modest and are accompanied by significant safety concerns, including amyloid-related imaging abnormalities (ARIA). Current pharmacological strategies predominantly rely on single-target mechanisms, an approach increasingly recognized as insufficient to address the multifactorial neurobiology of AD. This review critically evaluates the limitations of conventional amyloid-centric therapeutic strategies and contrasts them with emerging multi-target approaches based on phytochemicals. We synthesize current experimental and translational evidence to present a mechanistic framework illustrating how plant-derived bioactive compounds, including flavonoids and polyphenols, function as systems-level modulators of AD pathology rather than purely symptomatic agents. Particular emphasis is placed on their coordinated actions on amyloid processing via BACE1 inhibition, restoration of tau homeostasis through GSK-3β/PP2A regulation, attenuation of neuroinflammatory signaling, enhancement of endogenous antioxidant defenses through Nrf2 activation, and preservation of synaptic integrity. When considered collectively, the available evidence supports the concept that multi-target phytochemical strategies represent a biologically congruent and neurologically relevant paradigm for Alzheimer's disease therapy. Future progress will likely depend on integrating these compounds into broader polypharmacological and multidomain intervention frameworks, together with lifestyle-based strategies, repurposed drugs, anti-amyloid therapies, and rigorous translational validation.
Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuronal degeneration in the substantia nigra, in which lysosomal dysfunction and impaired autophagy-lysosome pathway activity are increasingly recognized as important pathogenic mechanisms. However, disease-modifying therapies targeting this pathway remain unavailable. Here, we generated induced pluripotent stem cells (iPSCs) from a PARK9 patient carrying an ATP13A2 mutation and established mutation-corrected isogenic control iPSCs. PARK9 iPSC-derived neurons recapitulated lysosomal dysfunction-associated cellular phenotypes, including impaired lysosomal acidification, reduced mature cathepsin D levels, CD63-positive vesicle accumulation, LC3B-positive autophagosome accumulation, cytoplasmic pSer129 α-synuclein accumulation, and increased cleaved caspase-3 signals. These phenotypes were ameliorated in mutation-corrected neurons, supporting the contribution of ATP13A2 dysfunction to these abnormalities. We then performed high-content imaging-based compound screening targeting LC3B-positive autophagosome accumulation in PARK9 neurons. A three-step workflow identified 19 candidate compounds that reduced autophagosome accumulation consistent with partial improvement of lysosome-dependent downstream autophagosome processing rather than simple suppression of autophagosome formation. Among these, paroxetine, Ro 25-6981, amisulpride, and PK11195 showed additional, compound-dependent effects on PARK9-associated phenotypes, including lysosomal acidification, CD63-positive vesicle accumulation, cytoplasmic pSer129 α-synuclein signals, and cleaved caspase-3 signals. These findings establish PARK9 iPSC-derived neurons as a useful model of lysosomal dysfunction-associated PD pathology and provide a practical screening platform for identifying candidate compounds that modulate autophagy-lysosome pathway-related cellular phenotypes.
The central catecholamine systems, norepinephrine and dopamine, play a critical role in encoding the valence of environmental stimuli to promote engagement in behaviors that potentiate an organism's survival. Furthermore, both neurochemicals in limbic brain areas such as the nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST) are major targets of stimulant drugs. Canonically, limbic norepinephrine signaling is enhanced in the presence of aversive or noxious stimuli whereas dopamine transmission is generally considered to increase in response to appetitive or rewarding stimuli. However, it remains to be elucidated whether sex differences, especially at different stages of the estrous cycle, distinctly regulate catecholamine transmission in vivo. In this study we (i) identified estrous cycle-dependent changes in catecholamine regulation via their transporters and autoreceptors in the BNST and NAc of anesthetized rats and (ii) determined how the psychostimulant methamphetamine (METH) impacts norepinephrine and dopamine transmission in the BNST and NAc, respectively, in male and freely cycling female rats using in vivo fast-scan cyclic voltammetry. Our results demonstrate electrically evoked BNST norepinephrine levels are increased by METH the greatest during the non-estrus (diestrus/proestrus) stages while NAc dopamine release evoked by electrical stimulation and METH is heightened in estrus. This limbic norepinephrine and dopamine regulation suggests a critical role of estrous cycle stage on catecholamine dynamics. These findings offer new insights into the role of estrous cycle stage on how the brain encodes environmental stimuli and provide a new framework for sex-specific therapies for targeting the central catecholamine systems in health and disease ranging from drug use disorders to obesity.
