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Progress in Neurobiology Jun 2024Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe...
Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases.
PubMed: 38945516
DOI: 10.1016/j.pneurobio.2024.102654 -
Biological Psychiatry Jun 2024Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can...
BACKGROUND
Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Since such qualities were found crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR.
METHODS
ELISA-based binding assay and NMR spectroscopy were accomplished to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to address whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis, and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75KO mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verifying how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male WT mice and rats.
RESULTS
Antidepressants were found binding to p75NTR, FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes.
CONCLUSION
We thus hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain ability for remodeling.
PubMed: 38945387
DOI: 10.1016/j.biopsych.2024.06.021 -
Schizophrenia Research Jun 2024Certain antipsychotics elevate prolactin levels in patients with schizophrenia spectrum disorders (SSD), potentially affecting cognition, symptoms, and hormone levels....
BACKGROUND
Certain antipsychotics elevate prolactin levels in patients with schizophrenia spectrum disorders (SSD), potentially affecting cognition, symptoms, and hormone levels. This study examines the association between prolactin, testosterone, and estrogen and cognition and symptoms in men with SSD, considering antipsychotic medication.
METHODS
This cross-sectional study included 128 men with SSD and 44 healthy men from two trials. Patients were divided into a prolactin-sparing (n = 53) and prolactin-raising group (n = 75) based on antipsychotic medication. We examined the association between hormones (testosterone, estrogen and prolactin), and cognition and symptoms using backward linear regression. Three domains of cognition were assessed including: processing speed, verbal fluency, and working memory, while symptoms were measured using the Positive and Negative Syndrome Scale (PANSS).
RESULTS
Prolactin levels were highest in the prolactin-raising group, followed by the control group, and lowest in the prolactin-sparing group (H = 45.279, p < .001). Testosterone and estrogen levels did not differ significantly between groups. In the prolactin-raising group, prolactin negatively correlated with testosterone (r(73) = -0.32, p = .005). Higher testosterone predicted better cognitive functioning (working memory: β = 0.20, p = .007, verbal fluency: β = 0.30, p = .001) and lower symptom scores (total: β = -0.21, p = .001; negative: β = -0.24, p = .002) in men with SSD. Conversely, higher estrogen levels related to slower processing speed (β = -0.22, p < .001) and higher symptoms scores (β = 0.23, p = .010) in men with SSD.
CONCLUSION
The results suggest positive associations between testosterone and cognition and symptoms in men with SSD, while suggesting that high prolactin levels could relate to lower testosterone levels, possibly worsening cognition and symptoms in men with SSD.
PubMed: 38944973
DOI: 10.1016/j.schres.2024.06.022 -
Brain and Behavior Jul 2024Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances...
Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.
INTRODUCTION
Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO.
METHODS
Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods.
RESULTS
The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor.
CONCLUSION
Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.
Topics: Animals; Isoflurane; Female; Cognitive Dysfunction; Pregnancy; Sleep Deprivation; Mice; Hippocampus; Prenatal Exposure Delayed Effects; Neuroinflammatory Diseases; Anesthetics, Inhalation; Synapses; Male; Mice, Inbred C57BL; Maternal Deprivation; Brain-Derived Neurotrophic Factor
PubMed: 38945806
DOI: 10.1002/brb3.3610 -
Neurotherapeutics : the Journal of the... Jun 2024Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique for modulating cortical activities and improving neural plasticity....
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique for modulating cortical activities and improving neural plasticity. Several studies investigated the effects of rTMS, etc., but the results are inconsistent. This study was designed to examine whether rTMS applied on the left dorsolateral prefrontal cortex (l-DLPFC) showed an effect on improving cognitive deficits in SZ and whether the early efficacy could predict efficacy at subsequent follow-ups. Cognitive ability was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale at baseline, weeks 2, 6, and 24. We found a significant interaction between time (weeks 0, 2, 6, and 24) and intervention on immediate memory and RBANS total scores (p = 0.02 and p = 0.04), indicating that both 10-Hz and 20-Hz rTMS stimulations had a delayed beneficial effect on immediate memory in SZ. Moreover, we found that 20-Hz rTMS stimulation, but not 10-Hz rTMS improved immediate memory at week 6 compared to the sham group (p = 0.029). More importantly, improvements in immediate memory at week 2 were positively correlated with improvements at week 24 (β = 0.461, t = 3.322, p = 0.002). Our study suggests that active rTMS was beneficial for cognitive deficits in patients with SZ. Furthermore, efficacy at week 2 could predict the subsequent efficacy at 24-week follow-up.
PubMed: 38944636
DOI: 10.1016/j.neurot.2024.e00392 -
Soins. Gerontologie 2024The recognition of caregivers working with elderly people with neuro-evolutionary diseases is a fact. The caregivers interviewed for this study reported that they felt...
The recognition of caregivers working with elderly people with neuro-evolutionary diseases is a fact. The caregivers interviewed for this study reported that they felt recognized and identified by these elderly people, who were considered to be prosopagnosic. The caregivers were even able to show that this recognition was possible, even during changes in appearance.
Topics: Humans; Caregivers; Aged; Male; Female; Neurocognitive Disorders; Middle Aged; Aged, 80 and over
PubMed: 38944467
DOI: 10.1016/j.sger.2024.04.006 -
Progress in Neuro-psychopharmacology &... Jun 2024Biological sex disparities manifest at various stages of drug addiction, including craving, substance abuse, abstinence, and relapse. These discrepancies are underpinned... (Review)
Review
Biological sex disparities manifest at various stages of drug addiction, including craving, substance abuse, abstinence, and relapse. These discrepancies are underpinned by notable distinctions in neurobiological substrates, encompassing brain structures, functions, and neurotransmitter systems implicated in drug addiction. Neuronal biomarkers, such as neurotransmitters, signaling proteins, and genes may be associated with the diagnosis, prognosis, and treatment outcomes in both biological sexes afflicted by drug abuse. Sex differences in the neural reward system, mainly through dopaminergic transmission during drug abuse, can be attributed to modifications in neurotransmitter systems and signaling pathways. This results in distinct patterns of neural activation and responsiveness to addictive substances in males and females. Sex hormones, the estrus/menstrual cycle, and cerebral neurochemistry contribute to the progression of psychological and physiological dependence in both male and female individuals grappling with addiction. Moreover, the alteration of sex hormone balance and neurotransmitter release plays a pivotal role in substance use disorders, subsequently modulating cognitive functions pertinent to reward, including memory formation, decision-making, and locomotor activity. Comparative investigations reveal distinctions in brain region volume, gene expression, neuronal firing, and circuitry in substance use disorders affecting individuals of both biological sexes. This review examines prevalent substance use disorders to elucidate the impact of sex hormones as therapeutic biomarkers on the mesocorticolimbic neurotransmitter systems via diverse mechanisms within the addicted brain. We underscore the imperative necessity of considering these variations to gain a deeper comprehension of addiction mechanisms and potentially discern sex-specific neuronal biomarkers for tailored therapeutic interventions.
PubMed: 38944334
DOI: 10.1016/j.pnpbp.2024.111068 -
Neuroscience and Biobehavioral Reviews Jun 2024Depersonalisation-derealisation disorder (DDD) is characterised by distressing experiences of separation from oneself and/or one's surroundings, potentially resulting... (Review)
Review
Depersonalisation-derealisation disorder (DDD) is characterised by distressing experiences of separation from oneself and/or one's surroundings, potentially resulting from alterations in affective, cognitive, and physiological functions. This systematic review aimed to synthesise current experimental evidence of relevance to proposed mechanisms underlying DDD, to appraise existing theoretical models, and to inform future research and theoretical developments. Studies were included if they tested explicit hypotheses in DDD samples, with experimental manipulations of at least one independent variable, alongside behavioural, subjective, neurological, affective and/or physiological dependent variables. Some evidence for diminished subjective responsivity to aversive images and sounds, and hyperactivation in neurocircuits associated with emotional regulation when viewing aversive images emerged, corroborating neurobiological models of DDD. Inconsistencies were present regarding behavioural and autonomic responsivity to facial expressions, emotional memory, and self-referential processing. Common confounds included small sample sizes, medication, and comorbidities. Alterations in affective reactivity and regulation appear to be present in DDD; however, further research employing more rigorous research designs is required to provide stronger evidence for these possible mechanisms.
PubMed: 38944228
DOI: 10.1016/j.neubiorev.2024.105783 -
Neuroscience and Biobehavioral Reviews Jun 2024Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive... (Review)
Review
Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive deficits that overlap between young autistic individuals and elderlies with dementia raise an important question: does compromised cognitive ability and brain structure during early development drive autistic adults to be more vulnerable to pathological aging conditions, or does it protect them from further decline? To answer this question, we have synthesized current theoretical models of aging in ASD and conducted a systematic literature review (Jan 1, 1980 - Feb 29, 2024) and meta-analysis to summarize empirical studies on cognitive and brain deviations in middle-to-old aged autistic adults. We explored findings that support different aging theories in ASD and addressed study limitations and future directions. This review sheds light on the poorly understood consequences of aging question raised by the autism community to pave the way for future studies to identify sensitive and reliable measures that best predict the onset, progression, and prognosis of pathological aging in ASD.
PubMed: 38944227
DOI: 10.1016/j.neubiorev.2024.105782 -
Biological Psychiatry Jun 2024Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and... (Review)
Review
Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and the thoughtful regulation of attention, action and emotion. For example, schizophrenia, depression, long-COVID and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often focused in layer III. The dlPFC has extensive top-down projections: e.g. to the posterior association cortices to regulate attention, and the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state, and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors in most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research, and are summarized in this review. For example, the layer III dlPFC circuits generating working memory-related neuronal firing have unusual neurotransmission, depending on NMDAR and nicotinic-α7R actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A-AR and mGluR3 signaling, but dysregulated by inflammation and/or chronic stress exposure, contributing to spine loss. Treatments that strengthen dlPFC, via pharmacological (the α2A-AR agonist, guanfacine) or rTMS manipulation, provide a rational basis for therapy.
PubMed: 38944141
DOI: 10.1016/j.biopsych.2024.06.016