Cells and circuits for amygdala neuroplasticity in the transition to chronic pain

Cell Reports, Год журнала: 2024, Номер 43(9), С. 114669 - 114669

Опубликована: Авг. 23, 2024

Maladaptive plasticity is linked to the chronification of diseases such as pain, but transition from acute chronic pain not well understood mechanistically. Neuroplasticity in central nucleus amygdala (CeA) has emerged a mechanism for sensory and emotional-affective aspects injury-induced although evidence comes studies conducted almost exclusively conditions agnostic cell type specificity. Here, we report time-dependent changes genetically distinct projection-specific CeA neurons neuropathic pain. Hyperexcitability CRF projection synaptic parabrachial (PB) input at stage shifted hyperexcitability without non-CRF phase. Accordingly, chemogenetic inhibition PB→CeA pathway mitigated pain-related behaviors acute, chronic, Cell-type-specific temporal neuroplasticity provide neurobiological clinical observation that simply prolonged persistence

Язык: Английский

---

Anxiety Disorders: Treatments, Models, and Circuitry Mechanisms

European Journal of Pharmacology, Год журнала: 2024, Номер 983, С. 176994 - 176994

Опубликована: Сен. 12, 2024

Язык: Английский

---

Depletion of HSP60 in Microglia Leads to Synaptic Dysfunction and Depression‐Like Behaviors Through Enhanced Synaptic Pruning in Male Mice

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(4)

Опубликована: Апрель 1, 2025

ABSTRACT Aims Microglia, as resident macrophages in the brain, play an important role depression. Heat shock protein 60 (HSP60), a chaperone protein, plays cell stress. However, of microglial HSP60 depression remains unclear. Methods CX3CR1‐CreER was used to generate microglial‐specific knockout (HSP60 cKO) mice. Behavioral tests, western blotting, Golgi staining, biochemical assays, and proteomics were employed assess depression‐like symptoms, activation, synaptic changes. Results cKO male mice exhibited depressive‐like behaviors, without anxiety‐like behavior, including increased immobility forced swimming tail suspension reduced sucrose preference, elevated corticosterone (CORT) levels, indicating HPA axis activation. Microglial activation confirmed by expression levels CD68 CD86, transcription cybb gene, branch complexity. Enhanced phagocytosis excitatory synapses, dendritic spine density, decreased glutamate observed, with downregulation proteins (AMPAR2, Synapsin‐1, PSD95), dysregulated pruning. Moreover, GO analysis showed 20 significant differentially expressed (DEPs) from are associated presynaptic endosome, which crucial maintaining function. Treatment PLX3397, CSF1R inhibitor, alleviated behaviors restored density Conclusions deletion microglia leads overactivation microglia, impaired function, highlighting importance homeostasis mood regulation potential therapeutic modulation.

Язык: Английский

---

Microglia specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice

Brain Behavior and Immunity, Год журнала: 2025, Номер 128, С. 383 - 399

Опубликована: Апрель 17, 2025

Язык: Английский

---

Stress-induced anxiety-related behavior in mice is driven by enhanced excitability of ventral tegmental area GABA neurons

Frontiers in Behavioral Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Июль 17, 2024

Introduction Stress and trauma are significant risk factors for many neuropsychiatric disorders diseases, including anxiety disorders. Stress-induced symptoms have been attributed to enhanced excitability in circuits controlling fear, anxiety, aversion. A growing body of evidence has implicated GABAergic neurons the ventral tegmental area (VTA) aversion processing affective behavior. Methods We used an unpredictable footshock (uFS) model, together with electrophysiological behavioral approaches, investigate role VTA GABA anxiety-related behavior mice. Results One day after a single uFS session, C57BL/6J mice exhibited elevated neuron excitability. The was correlated increased glutamatergic input reduction postsynaptic signaling mediated via B receptors. Chemogenetic activation sufficient increase stress-naïve In addition, chemogenetic inhibition suppressed exposed uFS. Discussion These data show that early substrate stress-induced suggest approaches mitigating may hold promise treatment provoked by stress trauma.

Язык: Английский

---

Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?

Biomolecules, Год журнала: 2024, Номер 14(9), С. 1087 - 1087

Опубликована: Авг. 30, 2024

The extracellular matrix plays a key role in synapse formation and the modulation of synaptic function central nervous system. Recent investigations have revealed that microglia, resident immune cells brain, are involved remodeling under both physiological pathological conditions. Moreover, dysregulation innate responses has been documented stress-related psychopathologies as well relation to early-life stress. However, dynamics microglial regulation ECM how it can be impacted by adversity understudied. This brief review provides an overview recent literature on this topic, drawing from animal model human post mortem studies. Direct indirect mechanisms through which microglia may regulate matrix-including perineuronal nets-are presented discussed light interactions with other cell types.

Язык: Английский

---

Role of chemokines in aging and age-related diseases

Mechanisms of Ageing and Development, Год журнала: 2024, Номер unknown, С. 112009 - 112009

Опубликована: Дек. 1, 2024

Язык: Английский

---

Facilitating microglia M2 polarization alleviates p-Synephrine-induced depressive-like behaviours in CSDS mice via the 5-HT6R-FYN-ERK1/2 pathway

International Immunopharmacology, Год журнала: 2024, Номер 147, С. 113926 - 113926

Опубликована: Дек. 31, 2024

In recent years, modulation of microglial phenotype transformation has emerged as a promising strategy for treating central nervous system disorders. Aurantii Fructus Immaturus (Zhishi), traditional Chinese medicine with versatile applications, contains p-Synephrine (p-SYN) its principal bioactive compound, recognized anti-inflammatory efficacy. However, the molecular mechanisms underlying these effects remain unclear. This study aimed to elucidate through which p-SYN modulates and alleviates neuroinflammation using both chronic social defeat stress (CSDS) model lipopolysaccharide-induced human cell (HMC-3) system. The antidepressant were assessed various behavioural tests including interaction, three-chambered sucrose preference, tail suspension, forced swimming, open field, novelty-suppressed feeding tests. Additionally, brain penetration was determined LC-MS. results indicated that mitigated CSDS-induced deficits depressive-like behaviours, lowered inflammatory responses, evidenced by decreased levels TNF-α IL-6 increased IL-10 levels. Moreover, reduced expression M1 markers CD86 iNOS, while increasing M2 Arg-1 CD206. Cellular thermal shift assay, drug affinity reaction target stabilization technology, co-immunoprecipitation demonstrated directly binds 5-hydroxytryptamine 6 receptor (5-HT6R), leading weakening 5-HT6R tyrosine kinase FYN interaction inhibiting 5-HT6R-FYN-ERK1/2 pathway. enhances production factors, subsequently shifts microglia phenotype, eventually mitigates neuroinflammation, thereby exhibiting properties.

Язык: Английский

---

Cpeb1 remodels cell type–specific translational program to promote fear extinction

Science Advances, Год журнала: 2025, Номер 11(2)

Опубликована: Янв. 10, 2025

Protein translation is crucial for fear extinction, a process vital adaptive behavior and mental health, yet the underlying cell-specific mechanisms remain elusive. Using Tet-On 3G genetic approach, we achieved precise temporal control over protein in infralimbic medial prefrontal cortex ( IL ) during extinction. In addition, our results reveal that disruption of cytoplasmic polyadenylation element binding 1 (Cpeb1) leads to notable alterations cell type–specific translational programs, thereby affecting Specifically, Cpeb1 deficiency neurons activates heterochromatin 3, which enhances microRNA networks, whereas microglia, it suppresses chemokine receptor Cx3cr1 ), resulting an aged-like microglial phenotype. These coordinated impair spine formation plasticity. Our study highlights critical role extinction provides insight into therapeutic targets disorders with deficits.

Язык: Английский

---

Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Abstract While CNS microglia have well-established roles in synapse pruning during neurodevelopment, only a few studies identified for formation. These focused on the cortex and primary sensory circuits restricted developmental time periods, leaving substantial gaps our understanding of early functions microglia. Here we investigated how absence impacts synaptic development nucleus accumbens (NAc), region critical emotional regulation motivated behaviors where dysfunction is implicated psychiatric disorders that arise life. Using genetically modified mouse lacks ( Csf1r ΔFIRE/ΔFIRE ), found blunted excitatory formation NAc. This effect was most prominent second third postnatal weeks, when previously to be overproduced, accompanied by an increase presynaptic release probability alterations postsynaptic kinetics. Tissue-level NAc proteomics confirmed microglial impacted numerous proteins involved structure, trans-synaptic signaling, pre-synaptic function. However, did not perturb levels astrocyte-derived cues adhesive promote synaptogenesis, suggesting reduced number may caused microglial-derived synaptogenic cue. Although observed electrophysiological changes were largely normalized adulthood, lasting effects threat avoidance behavior, these behavioral directly associated with neuronal activity. Together, results indicate role regulating landscape developing establishing functional underlying adult repertoires.

Язык: Английский

---