A humanized NOVA1 splicing factor alters mouse vocal communications

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 18, 2025

Abstract NOVA1, a neuronal RNA-binding protein expressed in the central nervous system, is essential for survival mice and normal development humans. A single amino acid change (I197V) NOVA1’s second RNA binding domain unique to modern To study its physiological effects, we generated carrying human-specific I197V variant ( Nova1 hu/hu ) analyzed molecular behavioral consequences. While substitution had minimal impact on capacity, it led specific effects alternative splicing, CLIP revealed multiple peaks mouse brain transcripts involved vocalization. These findings were associated with differences vocalization patterns as pups adults. Our suggest that this NOVA1 may have been part of an ancient evolutionary selective sweep common ancestral population Homo sapiens , possibly contributing spoken language through differential regulation during development.

Язык: Английский

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Central projections of nociceptive input originating from the low back and limb muscle in rats

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 20, 2025

Abstract Since clinical features of chronic muscle pain originating from the low back and limbs are different (higher prevalence broader/duller sensation than limb pain), spinal and/or supraspinal projection nociceptive information could differ between two muscles. We tested this hypothesis using c-Fos immunohistochemistry combined with retrograde-labeling dorsal horn (DH) neurons projecting to ventrolateral periaqueductal grey (vlPAG) or ventral posterolateral nucleus thalamus (VPL) by fluorogold (FG) injections into vlPAG VPL. C-Fos expression in DH was induced injecting 5% formalin multifidus (MF, back) gastrocnemius-soleus (GS, limb) muscle. A double-labeled neuron showing both c-Fos-immunoreactive retrogradely transported FG cytoplasm considered as a neuron. Consistent somatotopy for proximal vs. distal cutaneous inputs, MF input were located most lateral area laminae I − II (segments Th12 L5), while those GS middle (L3 L5). superficial DH, VPL deep DH. Supraspinal derived more segments input. These data suggest that muscles is integrated craniocaudal direction muscles, these signals then forwarded PAG contribute nature arising limbs.

Язык: Английский

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Activation of the periaqueductal gray controls respiratory output through a distributed brain network

Frontiers in Physiology, Год журнала: 2025, Номер 16

Опубликована: Янв. 22, 2025

Introduction The periaqueductal gray (PAG) has been previously established to play a key role in producing the vital changes respiration occurring response threat. However, it is not fully understood how PAG activation alters ongoing respiratory output, nor which pathways mediate these effects, as several regions have identified influence activity. Methods We used optogenetic tools conjunction with EMG recordings of inspiratory and expiratory musculature determine on short (250 ms) longer (10–15 s) timescales muscle Through cFOS mapping, we also downstream brain were likely modulated by including preBötzinger Complex (preBötC) lateral parafacial area (pFL). then stimulated terminals those whether their activity can account for observed effects stimulation. Results Directly stimulating resulted prominent all recorded activities reset breathing rhythm either phase-independent or phase-dependent manner. In contrast, preBötC pFL long shorter timescale stimuli could completely replicate direct stimulation did produce any reset. Conclusions Our results show that are mediated solely inputs more involve integration across larger network brainstem areas.

Язык: Английский

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Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats

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

Опубликована: Янв. 22, 2025

Psychosocial stressors are known to promote cocaine craving and relapse in humans but infrequently employed preclinical models. Consequently, the underlying neural circuitry by which these drive seeking has not been thoroughly explored. Using Fos expression analyses, we sought examine whether ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of brain's hypothalamic defense system, activated during psychosocial stress-induced seeking. Adult male female rats self-administered (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, 20, a tactile cue was present operant chamber that signaled impending social defeat stress (n=16, 8/sex), footshock (n=12, 6/sex), no-stress control condition 6/sex) immediately after session's conclusion. Responding subsequently extinguished, were tested for reinstatement re-exposure their stress/no-stress post-session event. All experimental groups displayed significant seeking, analyses indicated activity within rostrolateral PAG (rPAGl) selectively correlated with cocaine-seeking magnitude socially-defeated rats. rPAGl activation also associated active-defense coping behaviors encounters prelimbic prefrontal cortex orexin-negative cells lateral hypothalamus/perifornical area males, females. These findings suggest potentially novel role perhaps sex-dependent manner.

Язык: Английский

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Input–output organization of the mouse BLA-projecting IL neurons

Frontiers in Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Фев. 19, 2025

The infralimbic cortex (IL), a critical subregion within the ventromedial prefrontal (vmPFC), modulates emotion, memory, and social functions via robust projections to basolateral amygdala (BLA). However, afferent brain regions that innervate BLA-projecting IL neurons (IL-BLA PNs) their efferent targets have not been systematically characterized. We employed tracing techniques integrating adeno-associated virus (AAV) monosynaptic rabies investigate presynaptic inputs axonal outputs of IL-BLA PNs. Our findings revealed widespread synaptic PNs from subcortical areas, with strongest originating dorsomedial thalamus (MD) anterior medial (AM) in thalamic region, as well ventral hippocampus (vHPC) piriform (Pir) limbic system. Sparse labeling demonstrated collateralize various regions, including horizontal diagonal band (HDB), lateral preoptic area (LPO), pallidum (VP), hypothalamus (LH). This work establishes essential theoretical frameworks for functional investigation targeted intervention neurological disorders.

Язык: Английский

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The therapeutic application of hydrogels in chronic pain

Journal of Drug Delivery Science and Technology, Год журнала: 2025, Номер unknown, С. 106829 - 106829

Опубликована: Март 1, 2025

Язык: Английский

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Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD

Psychopharmacology, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Abstract Rationale Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine’s acute treatment effects post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for development of targeted interventions. Objectives systematic review examines pharmacokinetic pharmacodynamic ketamine PTSD, differentiating between immediate effects. Method A comprehensive search across databases (Web Science, Scopus, Global Health, PubMed) grey literature yielded 317 articles, where 29 met inclusion criteria. These included preclinical models clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, neural pathways (PROSPERO ID: CRD42024582874). Results We found accumulating evidence that ketamine, involve changes in GABA, glutamate, glutamine levels, trigger re-regulation BDNF, enhancing plasticity via such as TrkB PSD-95. Other influences also include c-Fos, GSK-3, HDAC, HCN1, modulation hormones like CHR ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained arise from remodulations prolonged expression. mTOR-mediated BDNF alterations GSK-3β, FkBP5, GFAP, ERK phosphorylation, epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC). Conclusion promote long-term stability key brain regions, contributing to benefits. Understanding behind ketamine’s is critical developing safe effective personalised treatments, potentially leading more recovery.

Язык: Английский

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Astrocytes in Rodent Anxiety-Related Behavior: Role of Calcium and Beyond

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(6), С. 2774 - 2774

Опубликована: Март 19, 2025

Anxiety is a physiological, emotional response that anticipates distal threats. When kept under control, anxiety beneficial response, helping animals to maintain heightened attention in environments with potential dangers. However, an overestimation of threats can lead excessive expression that, humans, may evolve into disorders. Pharmacological treatments show variable efficacy among patients, highlighting the need for more efforts better understand pathogenesis Mounting evidence suggests astrocytes, type glial cells, are active partners neurons brain circuits and regulation behaviors both physiological pathological conditions. In this review, I summarize current literature on role astrocytes from different regions modulating anxious states, goal exploring novel cerebral mechanisms identify innovative therapeutic targets treatment

Язык: Английский

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Do some people with a prolonged disorder of consciousness experience pain? A clinically focused narrative review and synthesis

Clinical Rehabilitation, Год журнала: 2025, Номер unknown

Опубликована: Апрель 13, 2025

Objective To investigate the hypothesis that people with a prolonged disorder of consciousness experience nociceptive pain. Method A non-systematic literature review into nature and neurophysiological basis pain likely function when someone has severe thalamocortical dysfunction; behavioural manifestations in who cannot communicate; how they relate to experience. Findings Consciousness depends on integrity is judged clinically by establishing person's behaviour extracting or using meaning. The also deduced from behaviour, including increased purposeless motor movements, facial expressions, non-verbal vocal expressions physiological (autonomic) changes such as tachycardia tear production. Extensive brainstem midbrain networks are activated pain, autonomic networks. Given their early evolution location, resist damage. appear intrinsically resilient, functioning damaged unless damage severe. Synthesis Someone usually intransitive (arousal) not dependent cortical cognitive processes may have retained occurrent mental states aroused. Nociceptive stimuli elicit automatic but behaviours typically associated These be responses this unpleasant state limited time show behaviours, no memory it. Conclusion unconscious person exhibiting response experiences without analysing its significance; unlikely anticipate remember

Язык: Английский

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Altered microglial plasticity in the periaqueductal grey of adolescent Mecp2-heterozygous mice following early-life stress

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Rett syndrome (RTT), a severe neurodevelopmental disorder primarily affecting girls, is commonly caused by MECP2 loss-of-function mutations. Key symptoms include motor impairments, typical hand stereotypies and intellectual disability. Moreover, although not thoroughly studied, anxiety, heightened stress sensitivity, aberrant pain perception are also an important component of the RTT phenotype. Emerging evidence suggests that early-life (ELS) worsens Mecp2-related phenotypic alterations in mice. Microglia, resident immune cells within central nervous system, play critical role pathophysiology, yet combined impact ELS Mecp2 deficiency on microglia has been studied. Previously, we observed reduced activation periaqueductal grey (PAG, cerebral structure involved modulation, autonomic control, defensive behaviours) Mecp2-heterozygous (Mecp2-het) mice after thermal stimulation. Here, investigated morphology PAG under deficiency. To this end, analysed presymptomatic Mecp2-het previously subjected to maternal separation (MS) as model ELS, alongside corresponding control animals. Brain sections were immunolabelled for IBA1, pan-microglial marker. Microglial evaluated expression levels, morphological characteristics, fractal properties. While global analyses showed minimal differences, subdivision-specific revealed significant microglial alterations. These findings suggest exacerbates deficits, impairing region-specific manner. Our data points failure morphologically adapt, rather than overt structural loss, may underlie some neurological dysfunctions RTT.

Язык: Английский

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