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Research Square May 2024Cellular senescence is a hallmark of aging and has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation drives cellular senescence;...
BACKGROUND
Cellular senescence is a hallmark of aging and has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation drives cellular senescence; however, the underlying mechanisms are unclear. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis. ABCA1 expression and its trafficking is afiltered in APOE4 and AD cellular and mouse models. However, whether ABCA1 trafficking is involved in cellular senescence in APOE4 and AD remains unknown.
METHODS
We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. An unbiased proteomic screening was performed to identify targets that mediate cellular ABCA1 trafficking. APOE4-TR mice, immortalized, primary and induced pluripotent stem cell (iPSC) models were used to examine the cholesterol-ABCA1-senescence pathways.
RESULTS
Bulk and single nuclei transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) revealed upregulation of cellular senescence transcriptome signatures in AD, which was strongly correlated with ABCA1 expression. Immunofluorescence and immunoblotting analyses confirmed increased ABCA1 expression in AD brain tissues, which was associated with lipofuscin-stained lipids and mTOR phosphorylation. Using discovery proteomics, caveolin-1, a sensor of cellular cholesterol accumulation, was identified to promote ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was found in both APOE4-TR mouse models and AD human brains. Cholesterol induced mTORC1 activation was regulated by ABCA1 expression or its lysosomal trapping. Reducing cholesterol by cyclodextrin in APOE4-TR mice reduced ABCA1 lysosome trapping and increased ABCA1 recycling to efflux cholesterol to HDL particles, reducing mTORC1 activation and senescence-associated neuroinflammation. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses.
CONCLUSIONS
Cholesterol accumulation in APOE4 and AD induced caveolin-1 expression, which traps ABCA1 in lysosomes to activate mTORC1 pathways and induce cellular senescence. This study provided novel insights into how cholesterol accumulation in APOE4 and AD accelerates senescence.
PubMed: 38798644
DOI: 10.21203/rs.3.rs-4373201/v1 -
BioRxiv : the Preprint Server For... May 2024The ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to...
The ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to identical word retrieval, the exact neural dynamics supporting this convergence relevant to daily auditory discourse remain poorly understood. Here, we leveraged neurosurgical electrocorticographic (ECoG) recordings from 48 patients and dissociated two key language networks that highly overlap in time and space integral to word retrieval. Using unsupervised temporal clustering techniques, we found a semantic processing network located in the middle and inferior frontal gyri. This network was distinct from an articulatory planning network in the inferior frontal and precentral gyri, which was agnostic to input modalities. Functionally, we confirmed that the semantic processing network encodes word surprisal during sentence perception. Our findings characterize how humans integrate ongoing auditory semantic information over time, a critical linguistic function from passive comprehension to daily discourse.
PubMed: 38798614
DOI: 10.1101/2024.05.15.594403 -
BioRxiv : the Preprint Server For... May 2024Adaptive decision making relies on dynamic updating of learned associations where environmental cues come to predict positive and negatively valenced stimuli, such as...
Adaptive decision making relies on dynamic updating of learned associations where environmental cues come to predict positive and negatively valenced stimuli, such as food or threat. Flexible cue-guided behaviors depend on a network of brain systems, including dopamine signaling in the striatum, which is critical for learning and maintenance of conditioned behaviors. Critically, it remains unclear how dopamine signaling encodes multi-valent, dynamic learning contexts, where positive and negative associations must be rapidly disambiguated. To understand this, we employed a Pavlovian discrimination paradigm, where cues predicting positive and negative outcomes were intermingled during conditioning sessions, and their meaning was serially reversed across training. We found that rats readily distinguished these cues, and updated their behavior rapidly upon valence reversal. Using fiber photometry, we recorded dopamine signaling in three major striatal subregions -,the dorsolateral striatum (DLS), the nucleus accumbens core, and the nucleus accumbens medial shell - and found heterogeneous responses to positive and negative conditioned cues and their predicted outcomes. Valence ambiguity introduced by cue reversal reshaped striatal dopamine on different timelines: nucleus accumbens core and shell signals updated more readily than those in the DLS. Together, these results suggest that striatal dopamine flexibly encodes multi-valent learning contexts, and these signals are dynamically modulated by changing contingencies to resolve ambiguity about the meaning of environmental cues.
PubMed: 38798567
DOI: 10.1101/2024.05.17.594692 -
MedRxiv : the Preprint Server For... May 2024DNA repetitive sequences (or repeats) comprise over 50% of the human genome and have a crucial regulatory role, specifically regulating transcription machinery. The...
DNA repetitive sequences (or repeats) comprise over 50% of the human genome and have a crucial regulatory role, specifically regulating transcription machinery. The human brain is the tissue with the highest detectable repeat expression and dysregulations on the repeat activity are related to several neurological and neurodegenerative disorders, as repeat-derived products can stimulate a pro-inflammatory response. Even so, it is unclear how repeat expression acts on the aging neurotypical brain. Here, we leverage a large postmortem transcriptome cohort spanning the human lifespan to assess global repeat expression in the neurotypical brain. We identified 21,696 differentially expressed repeats (DERs) that varied across seven age bins (Prenatal; 0-15; 16-29; 30-39; 40-49; 50-59; 60+) across the caudate nucleus (n=271), dorsolateral prefrontal cortex (n=304), and hippocampus (n=310). Interestingly, we found that long interspersed nuclear elements and long terminal repeats (LTRs) DERs were the most abundant repeat families when comparing infants to early adolescence (0-15) with older adults (60+). Of these differentially regulated LTRs, we identified 17 shared across all brain regions, including increased expression of HERV-K-int in older adult brains (60+). Co-expression analysis from each of the three brain regions also showed repeats from the HERV subfamily were intramodular hubs in its subnetworks. While we do not observe a strong global relationship between repeat expression and age, we identified HERV-K as a repeat signature associated with the aging neurotypical brain. Our study is the first global assessment of repeat expression in the neurotypical brain.
PubMed: 38798538
DOI: 10.1101/2024.05.17.24307184 -
Hearing Research Aug 2024Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential...
Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential aspect of binaural hearing: the ability of animals to localize the sources of low-frequency sounds by detecting the interaural time difference (ITD), that is the difference in the time at which the sound arrives at each ear. In mammals, ITDs are mostly encoded in the medial superior olive (MSO), one of the main nuclei of the superior olivary complex (SOC). Because of their small heads and high frequency hearing range, rats and mice are often considered unable to use ITDs for sound localization. Moreover, their MSO is frequently viewed as too small or insignificant compared to that of mammals that use ITDs to localize sounds, including cats and gerbils. However, recent research has demonstrated remarkable similarities between most morphological and physiological features of mouse MSO neurons and those of MSO neurons of mammals that use ITDs. In this context, we have analyzed the structure and neural afferent and efferent connections of the rat MSO, which had never been studied by injecting neuroanatomical tracers into the nucleus. The rat MSO spans the SOC longitudinally. It is relatively small caudally, but grows rostrally into a well-developed column of stacked bipolar neurons. By placing small, precise injections of the bidirectional tracer biotinylated dextran amine (BDA) into the MSO, we show that this nucleus is innervated mainly by the most ventral and rostral spherical bushy cells of the anteroventral cochlear nucleus of both sides, and by the most ventrolateral principal neurons of the ipsilateral medial nucleus of the trapezoid body. The same experiments reveal that the MSO densely innervates the most dorsolateral region of the central nucleus of the inferior colliculus, the central region of the dorsal nucleus of the lateral lemniscus, and the most lateral region of the intermediate nucleus of the lateral lemniscus of its own side. Therefore, the MSO is selectively innervated by, and sends projections to, neurons that process low-frequency sounds. The structural and hodological features of the rat MSO are notably similar to those of the MSO of cats and gerbils. While these similarities raise the question of what functions other than ITD coding the MSO performs, they also suggest that the rat MSO is an appropriate model for future MSO-centered research.
Topics: Animals; Superior Olivary Complex; Auditory Pathways; Sound Localization; Axons; Rats; Male; Dextrans; Biotin; Acoustic Stimulation; Efferent Pathways; Olivary Nucleus; Female; Neuroanatomical Tract-Tracing Techniques; Rats, Wistar
PubMed: 38797037
DOI: 10.1016/j.heares.2024.109036 -
Asian Journal of Psychiatry Jul 2024This study registered consecutive cases to elucidate the efficacy of rTMS treatment for depression within the Japanese public health insurance system. Of the 102...
This study registered consecutive cases to elucidate the efficacy of rTMS treatment for depression within the Japanese public health insurance system. Of the 102 patients with depression who received rTMS over the left dorsolateral prefrontal cortex, 44 (43.1 %) patients reached remission and 14 (13.7 %) patients did not reach remission but responded to treatment. No serious adverse events occurred. Low baseline HAMD-17 score was associated with remission after rTMS treatment. Favorable outcomes of rTMS treatment were shown in this cohort within the Japanese public insurance system. Our results provide insights into rTMS treatment for depression in real-world clinical setting.
Topics: Humans; Male; Female; Middle Aged; Japan; Transcranial Magnetic Stimulation; Adult; Registries; Aged; Treatment Outcome; Dorsolateral Prefrontal Cortex; Depressive Disorder, Major; Insurance, Health; East Asian People
PubMed: 38795414
DOI: 10.1016/j.ajp.2024.104082 -
Nutrients May 2024Binge eating disorder (BED) is the most common eating disorder among those contributing to the development of obesity, and thus acts as a significant burden on the lives... (Review)
Review
INTRODUCTION
Binge eating disorder (BED) is the most common eating disorder among those contributing to the development of obesity, and thus acts as a significant burden on the lives and health of patients. It is characterized by complex neurobiology, which includes changes in brain activity and neurotransmitter secretion. Existing treatments are moderately effective, and so the search for new therapies that are effective and safe is ongoing.
AIM AND METHODS
This review examines the use of transcranial direct current stimulation (tDCS) in the treatment of binge eating disorder. Searches were conducted on the PubMed/Medline, Research Gate, and Cochrane databases.
RESULTS
Six studies were found that matched the review topic. All of them used the anodal stimulation of the right dorsolateral prefrontal cortex (DLPFC) in BED patients. tDCS proved effective in reducing food cravings, the desire to binge eat, the number of binging episodes, and food intake. It also improved the outcomes of inhibitory control and the treatment of eating disorder psychopathology. The potential mechanisms of action of tDCS in BED are explained, limitations in current research are outlined, and recommendations for future research are provided.
CONCLUSIONS
Preliminary evidence suggests that the anodal application of tDCS to the right DLPFC reduces the symptoms of BED. However, caution should be exercised in the broader use of tDCS in this context due to the small number of studies performed and the small number of patients included. Future studies should incorporate neuroimaging and neurophysiological measurements to elucidate the potential mechanisms of action of tDCS in BED.
Topics: Female; Humans; Binge-Eating Disorder; Craving; Dorsolateral Prefrontal Cortex; Prefrontal Cortex; Transcranial Direct Current Stimulation; Treatment Outcome; Male
PubMed: 38794759
DOI: 10.3390/nu16101521 -
Brain Sciences May 2024Despite the availability of pharmacotherapy and psychotherapy for treating obsessive-compulsive disorder (OCD), alternative approaches need to be explored due to the...
Neuronavigated Right Orbitofrontal 20 Hz Theta Burst Transcranial Magnetic Stimulation Augmentation for Obsessive-Compulsive Disorder with Comorbid Depression and Anxiety Disorders: An Open-Label Study.
BACKGROUND
Despite the availability of pharmacotherapy and psychotherapy for treating obsessive-compulsive disorder (OCD), alternative approaches need to be explored due to the high likelihood of treatment resistance. Neuronavigated 20 Hz theta burst stimulation (TBS-20 Hz), targeting the bilateral dorsolateral prefrontal cortex (DLPFC) augmented with the right orbitofrontal cortex (ROFC), was tested for treating OCD comorbid with depression and anxiety disorders.
METHODS
A retrospective chart review was performed on fourteen patients treated for moderate-to-severe OCD in a private outpatient clinic. Twelve patients had comorbid major depressive disorder (MDD), and thirteen patients had either generalized anxiety disorder (GAD) or panic disorder (PD). Patients completed the Y-BOCS-SR, BDI-II, and BAI rating scales weekly, which were used to measure the changes in OCD, depression, and anxiety symptoms, respectively.
RESULTS
Neuronavigated TBS-20 Hz was sequentially applied to the right DLPFC (RDLPFC), left DLPFC (LDLPFC), and ROFC. A total of 64% (9/14) of patients achieved remission from OCD (Y-BOCS-SR ≤ 14) in an average of 6.1 weeks of treatment (SD = 4.0). A total of 58% (7/12) of patients remitted from MDD (BDI < 13) in an average of 4.1 weeks (SD = 2.8), and 62% (8/13) of patients remitted from GAD/PD (BAI < 8) in an average of 4.3 weeks (SD = 2.5).
CONCLUSIONS
The neuronavigated TBS-20 Hz sequential stimulation of RDLPFC and LDLPFC, followed by ROFC, significantly reduced OCD, MDD, and GAD/PD symptoms. Randomized sham controls are warranted to validate these results.
PubMed: 38790461
DOI: 10.3390/brainsci14050483 -
Brain Sciences Apr 2024Few randomized controlled trials have reported that repetitive transcranial magnetic stimulation (rTMS) has controversial results for managing multiple domains of...
Impact of Repetitive Transcranial Magnetic Stimulation on Cognitive and Psychiatric Dysfunction in Patients with Fibromyalgia: A Double-Blinded, Randomized Clinical Trial.
Few randomized controlled trials have reported that repetitive transcranial magnetic stimulation (rTMS) has controversial results for managing multiple domains of fibromyalgia-related symptoms. This work aimed to evaluate the effect of low-frequency rTMS over the right dorsolateral prefrontal area (DLPFC) on the Fibromyalgia Impact Questionnaire (FIQ) concerning psychiatric and cognitive disorders. Forty-two eligible patients with fibromyalgia (FM) were randomized to have 20 sessions of active or sham rTMS (1 Hz, 120% of resting motor threshold with a total of 1200 pules/session) over the right DLPFC. All participants were evaluated at baseline, post sessions, and 3 months after sessions with the FIQ, Hamilton depression, and anxiety rating scales (HDRS and HARS), Montreal Cognitive Assessment (MoCA), Rey Auditory Verbal Learning Test (RAVLT), Tower of London test (TOL), the Trail Making, and Digit Span Tests. Both groups showed improvement in most rating scales at 1 and 3 months follow-up, with greater improvement in the active group, with significant correlation between FIQ cognitive rating scales, including RAVLT and TOL. Twenty sessions of low-frequency rTMS over the right DLPFC can improve FIQ scores regarding the psychiatric and cognitive symptoms of medicated patients with FM to a greater extent than sham. Changes in RAVLT and TOL correlated with changes in FIQ results.
PubMed: 38790395
DOI: 10.3390/brainsci14050416 -
Journal of Affective Disorders Sep 2024rTMS is a safe and effective intervention for treatment-resistant depression (TRD). However, there is limited data on its specific impact on suicidal ideation (SI), and... (Clinical Trial)
Clinical Trial
BACKGROUND
rTMS is a safe and effective intervention for treatment-resistant depression (TRD). However, there is limited data on its specific impact on suicidal ideation (SI), and the trajectory of SI over the treatment course.
OBJECTIVE
This open-label clinical trial investigated SI outcomes and trajectories in patients with TRD receiving low-frequency rTMS (LFR) to the right dorsolateral prefrontal cortex (DLPFC; N = 55).
METHODS
A latent class mixed-effect model was used to identify response trajectories for SI as well as core mood symptoms. Logistic regression analyses investigated risk factors associated with identified trajectories.
RESULTS
For each symptom domain, we identified two distinct trajectories during LFR, one tracking improvement (SI: n = 35, 60 %; mood: n = 29, 53 %) and the other tracking no improvement (SI: n = 20, 40 %; mood: n = 26, 47 %). Male sex, higher baseline anxiety, and higher baseline SI were risk factors for no improvement of SI; while higher baseline anxiety and benzodiazepine use were risk factors for no improvement of mood. Mediation analyses showed that anxiety was a risk factor for no improvement of SI and mood independent of benzodiazepine treatment.
CONCLUSIONS
This is the first study to investigate trajectories of response to LFR to the right DLPFC. SI and mood improved with LFR in most patients but the severity of anxiety symptoms was a factor of poor prognosis for both. Nuanced characterization of SI response to rTMS may lead to critical insights for individualized targeting strategies.
Topics: Humans; Male; Suicidal Ideation; Female; Depressive Disorder, Treatment-Resistant; Transcranial Magnetic Stimulation; Middle Aged; Adult; Risk Factors; Dorsolateral Prefrontal Cortex; Anxiety; Treatment Outcome; Affect
PubMed: 38788857
DOI: 10.1016/j.jad.2024.05.109