Modulation Of Neuroplasticity Research Articles

Ultrasound-Triggered NO Release to Promote Axonal Regeneration for Noise-Induced Hearing Loss Therapy.

Intense noise poses a threat to spiral ganglion neurons (SGNs) in the inner ear, often resulting in limited axonal regeneration during noise injury and leading to noise-induced hearing loss (NIHL). Here, we propose an ultrasound-triggered nitric oxide (NO) release to enhance the sprouting and regeneration of injured axons in SGNs. We developed hollow silicon nanoparticles to load nitrosylated N-acetylcysteine, producing HMSN-SNO, which effectively protects NO from external interferences. Utilizing low-intensity ultrasound stimulation with bone penetration, we achieve the controlled release of NO from HMSN-SNO within the cochlea. In mice with NIHL, a rapid and extensive loss of synaptic connections between hair cells and SGNs is observed within 24 h after exposure to excessive noise. However, this loss could be reversed with the combined treatment, resulting in a hearing functional recovery from 83.57 to 65.00 dB SPL. This positive outcome is attributed to the multifunctional effects of HMSN-SNO, wherein they scavenge reactive oxygen species (ROS) to reverse the pathological microenvironment and simultaneously upregulate the CREB/BDNF/EGR1 signaling pathway, thereby enhancing neuroplasticity and promoting the regeneration of neuronal axons. These findings underscore the potential of nanomedicine for neuroplasticity modulation, which holds promise for advancing both basic research and the further treatment of neurological diseases.

High Mobility Group Box-1 (HMGB1), a Key Mediator of Cognitive Decline in Neurotrauma with a Potential for Targeted Therapy: A Comprehensive Review.

Neurotrauma plays a significant role in secondary injuries by intensifying the neuroinflammatory response in the brain. High Mobility Group Box-1 (HMGB1) protein is a crucial neuroinflammatory mediator involved in this process. Numerous studies have hypothesized about the underlying pathophysiology of HMGB1 and its role in cognition, but a definitive link has yet to be established. Elevated levels of HMGB1 in the hippocampus and serum have been associated with declines in cognitive performance, particularly in spatial memory and learning. This review also found that inhibiting HMGB1 can improve cognitive deficits following neurotrauma. Interestingly, HMGB1 levels are linked to the modulation of neuroplasticity and may offer neuroprotective effects in the later stages of neurotraumatic events. Consequently, administering HMGB1 during the acute phase may help reduce neuroinflammatory effects that lead to cognitive deficits in the later stages of neurotrauma. However, further research is needed to understand the time-dependent regulation of HMGB1 and the clinical implications of treatments targeting HMGB1 after neurotrauma.

Role of STAT3-FOXO3 Signaling in the Modulation of Neuroplasticity by PD-L1-HGF-Decorated Mesenchymal Stem Cell-Derived Exosomes in a Murine Stroke Model.

The limited therapeutic strategies available for stroke leave many patients disabled for life. This study assessed the potential of programmed death-ligand 1 (PD-L1) and hepatocyte growth factor (HGF)-engineered mesenchymal stem cell-derived exosomes (EXO-PD-L1-HGF) in enhancing neurological recovery post-stroke. EXO-PD-L1-HGF, which efficiently endocytosed into target cells, significantly diminishes the H2O2-induced neurotoxicity and increased the antiapoptotic proteins in vitro. EXO-PD-L1-HGF attenuates inflammation by inhibiting T-cell proliferation and increasing the number of CD8+CD122+IL-10+ regulatory T cells. Intravenous injection of EXO-PD-L1-HGF could target stromal cell-derived factor-1α (SDF-1α+) cells over the peri-infarcted area of the ischemic brain through CXCR4 upregulation and accumulation in neuroglial cells post-stroke. EXO-PD-L1-HGF facilitates endogenous nestin+ neural progenitor cell (NPC)-induced neurogenesis via STAT3-FOXO3 signaling cascade, which plays a pivotal role in cell survival and neuroprotection, thereby mitigating infarct size and enhancing neurological recovery in a murine stroke model. Moreover, increasing populations of the immune-regulatory CD19+IL-10+ and CD8+CD122+IL-10+ cells, together with reducing populations of proinflammatory cells, created an anti-inflammatory microenvironment in the ischemic brain. Thus, innovative approaches employing EXO-PD-L1-HGF intervention, which targets SDF-1α+ expression, modulates the immune system, and enhances the activation of resident nestin+ NPCs, might significantly alter the brain microenvironment and create a niche conducive to inducing neuroplastic regeneration post-stroke.

The therapeutic potential of traditional Chinese medicine in depression: focused on the modulation of neuroplasticity.

Depression, a mood disorder characterized by a persistent low mood and lack of enjoyment, is considered the leading cause of non-fatal health losses worldwide. Neuroplasticity refers to the brain's ability to adapt to external or internal stimuli, resulting in functional and structural changes. This process plays a crucial role in the development of depression. Traditional Chinese Medicine (TCM) shows significant potential as a complementary and alternative therapy for neurological diseases, including depression. However, there has been no systematic summary of the role of neuroplasticity in the pathological development of depression and TCM Interventions currently. This review systematically summarized recent literature on changes in neuroplasticity in depression and analyzed the regulatory mechanisms of active metabolites in TCM and TCM formulas on neuroplasticity in antidepressant treatment. Additionally, this review discussed the limitations of current research and the application prospects of TCM in regulating neuroplasticity in antidepressant research.

Lifestyle Modulators of Neuroplasticity in Parkinson's Disease: Evidence in Human Neuroimaging Studies.

Parkinson's disease (PD) is a neurodegenerative disease characterized by both motor and non-motor symptoms. A progressive neuronal loss and the consequent clinical impairment lead to deleterious effects on daily living and quality of life. Despite effective symptomatic therapeutic approaches, no disease-modifying therapies are currently available. Emerging evidence suggests that adopting a healthy lifestyle can improve the quality of life of PD patients. In addition, modulating lifestyle factors can positively affect the microstructural and macrostructural brain levels, corresponding to clinical improvement. Neuroimaging studies may help to identify the mechanisms through which physical exercise, dietary changes, cognitive enrichment, and exposure to substances modulate neuroprotection. All these factors have been associated with a modified risk of developing PD, with attenuation or exacerbation of motor and non-motor symptomatology, and possibly with structural and molecular changes. In the present work, we review the current knowledge on how lifestyle factors influence PD development and progression and the neuroimaging evidence for the brain structural, functional, and molecular changes induced by the adoption of positive or negative lifestyle behaviours.

Immunological predictors of rhythmic transcranial magnetic stimulation (rTMS) efficiency in patients with treatment-resistant schizophrenia

IntroductionModel and clinical studies demonstrate the efficiency of rhythmic transcranial magnetic stimulation (rTMS) in diseases associated with neuroinflammation. The therapeutic potential of rTMS is related to modulation of neuroplasticity in the CNS, activation of neurogenesis and reduction of neuroinflammatory processes. Presumably, one of the factors that determines the efficiency of rTMS can be the features of the immune status of patients.ObjectivesTo reveal the features of the spectrum of inflammatory markers in patients with treatment-resistant schizophrenia with different efficiency of rTMS.Methods 31 male patients aged 16 to 47 years (mean age 29.9 ± 8.4 years) with treatment-resistant schizophrenia who developed a first psychotic episode in adolescence (19-25 years) were examined. The course of rTMS was conducted for 3 weeks (15 sessions). Depending on the dynamics of clinical and psychometric parameters after the course of rTMS, the patients were divided into three groups: group 1 - with worsening of clinical condition (n=8); group 2 - without therapeutic effect (n=12); group 3 - with good therapeutic response (n=11). Before rTMS, leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) activity, and the levels of autoantibodies to S-100B protein and myelin basic protein (MBP) in the plasma of patients were determined. The parameters of 18 healthy male donors without clinical signs of psychiatric and somatic pathology were used as controls.ResultsAll groups of patients were characterised by moderate and high levels of immune system activation, determined by a complex of inflammatory and autoimmune markers. At the same time, the high level of immune system activation in patients with low MTR efficiency was associated with low LE activity in plasma (within the reference range or below the lower limit - 200.6 (168.5- 220.3) nmol/min·mL), which was not consistent with the overall level of inflammation. This group of patients also showed high levels of antibodies to MBP compared to control values (p<0.05). The low LE activity can be explained by the transmigration of neutrophils from the blood to the brain due to a critical increase in the permeability of the blood-brain barrier, which is largely controlled by LE.ConclusionsThe study confirmed the participation of immune mechanisms in the formation of therapeutic resistance in schizophrenia and revealed the characteristics of the spectrum of immune markers in patients with low efficiency of rTMS.Disclosure of InterestNone Declared

Neurochemical mechanisms underlying serotonergic modulation of neuroplasticity in humans

BackgroundStudies in animals and humans have shown that cortical neuroplasticity can be modulated by increasing serotonin levels by administering selective serotonin reuptake inhibitors (SSRI). However, little is known about the mechanistic background, especially the contribution of intracortical inhibition and facilitation, which depend on gamma-aminobutyric acid (GABA) and glutamate. ObjectiveWe aimed to explore the relevance of drivers of plasticity (glutamate- and GABA-dependent processes) for the effects of serotonin enhancement on tDCS-induced plasticity in healthy humans. MethodsA crossover, partially double-blinded, randomized, and sham-controlled study was conducted in 21 healthy right-handed individuals. In each of the 7 sessions, plasticity was induced via transcranial direct current stimulation (tDCS). Anodal, cathodal, and sham tDCS were applied to the left motor cortex under SSRI (20 mg/40 mg citalopram) or placebo. Short-interval cortical inhibition (SICI) and intracortical facilitation (ICF) were monitored by paired-pulse transcranial magnetic stimulation for 5–6 h after intervention. ResultsUnder placebo, anodal tDCS-induced LTP-like plasticity decreased SICI and increased ICF. In contrast, cathodal tDCS-elicited LTD-like plasticity induced the opposite effect. Under 20 mg and 40 mg citalopram, anodal tDCS did not affect SICI largely, while ICF was enhanced and prolonged. For cathodal tDCS, citalopram converted the increase of SICI and decrease of ICF into antagonistic effects, and this effect was dosage-dependent since it lasted longer under 40 mg when compared to 20 mg. ConclusionWe speculate that the main effects of acute serotonergic enhancement on tDCS-induced plasticity, the increase and prolongation of LTP-like plasticity effects, involves mainly the glutamatergic system.

The impact of purine nucleosides on neuroplasticity in the adult brain.

Neuroplasticity refers to the nervous system's ability to adapt and reorganize its cell structures and neuronal networks in response to internal and external stimuli. In adults, this process involves neurogenesis, synaptogenesis, and synaptic and neurochemical plasticity. Several studies have reported the significant impact of the purinergic system on neuroplasticity modulation. And, there is considerable evidence supporting the role of purine nucleosides, such as adenosine, inosine, and guanosine, in this process. This review presents extensive research on how these nucleosides enhance the neuroplasticity of the adult central nervous system, particularly in response to damage. The mechanisms through which these nucleosides exert their effects involve complex interactions with various receptors and signaling pathways. Adenosine's influence on neurogenesis involves interactions with adenosine receptors, specifically A1R and A2AR. A1R activation appears to inhibit neuronal differentiation and promote astrogliogenesis, while A2AR activation supports neurogenesis, neuritogenesis, and synaptic plasticity. Inosine and guanosine positively impact cell proliferation, neurogenesis, and neuritogenesis. Inosine seems to modulate extracellular adenosine levels, and guanosine might act through interactions between purinergic and glutamatergic systems. Additionally, the review discusses the potential therapeutic implications of purinergic signaling in neurodegenerative and neuropsychiatric diseases, emphasizing the importance of these nucleosides in the neuroplasticity of brain function and recovery.

Perinatal Depression and the Role of Synaptic Plasticity in Its Pathogenesis and Treatment.

Emerging evidence indicates that synaptic plasticity is significantly involved in the pathophysiology and treatment of perinatal depression. Animal models have demonstrated the effects of overstimulated or weakened synapses in various circuits of the brain in causing affective disturbances. GABAergic theory of depression, stress, and the neuroplasticity model of depression indicate the role of synaptic plasticity in the pathogenesis of depression. Multiple factors related to perinatal depression like hormonal shifts, newer antidepressants, mood stabilizers, monoamine systems, biomarkers, neurotrophins, cytokines, psychotherapy and electroconvulsive therapy have demonstrated direct and indirect effects on synaptic plasticity. In this review, we discuss and summarize the various patho-physiology-related effects of synaptic plasticity in depression. We also discuss the association of treatment-related aspects related to psychotropics, electroconvulsive therapy, neuromodulation, psychotherapy, physical exercise and yoga with synaptic plasticity in perinatal depression. Future insights into newer methods of treatment directed towards the modulation of neuroplasticity for perinatal depression will be discussed.

Bilayered Oxide Heterostructure‐Mediated Capacitance‐Based Neuroplasticity Modulation for Neuromorphic Classification

AbstractTo overcome the limitations of memristors in neuromorphic computation, memcapacitors are gaining attention owing to their scalability, low power dissipation, and sneak‐path‐free nature. This study focuses on the progressive capacitive switching of a bilayered metal‐oxide WOx/ZrOx heterojunction memcapacitor. To gain a better understanding of the interfacial switching behavior, density functional theory simulations are used to analyze the defects and oxide formation energy of the heterostructure. The memcapacitive characteristics are studied using the capacitance–voltage curves under different voltage‐sweeping conditions and impedance analysis. The memcapacitive characteristics can be attributed to the trapping of carriers in the depletion region of the WOx/ZrOx heterojunction, which is modulated by the relocation of oxygen vacancies under the electric field. The device exhibits a wider dynamic range of capacitance values than other metal‐oxide memcapacitors reported, and demonstrates versatile synaptic functions, such as potentiation/depression behavior, paired‐pulse facilitation, experience‐dependent plasticity, and learning–relearning behavior. Furthermore, an accuracy of 99.01% is achieved in handwritten digit classification using the capacitive state as the weight through a computing‐in‐memory emulator. The results affirm the applicability of the WOx/ZrOx memcapacitor in future capacitive neural networks.

Effect of current direction and muscle activation on motor cortex neuroplasticity induced by repetitive paired-pulse transcranial magnetic stimulation.

Repetitive paired-pulse transcranial magnetic stimulation (TMS) at indirect (I)-wave periodicity (iTMS) can increase plasticity in primary motor cortex (M1). Both TMS coil orientation and muscle activation can influence I-wave activity, but it remains unclear how these factors influence M1 plasticity with iTMS. We therefore investigated the influence of TMS coil orientation and muscle activation on the response to iTMS. Thirty-two young adults (24.2 ± 4.8years) participated in three experiments. Each experiment included two sessions using a modified iTMS intervention with either a posterior-anterior orientation (PA) or anterior-posterior (AP) coil orientation over M1. Stimulation was applied in resting (Experiments 1 and 3) or active muscle (Experiments 2 and 3). Effects of iTMS on M1 excitability were assessed by recording motor evoked potentials (MEPs) and short-interval intracortical facilitation (SICF) with PA and AP orientations in both resting (all experiments) and active (Experiment 2) muscle. For the resting intervention, MEPs were greater after AP iTMS (Experiment 1, P = .046), whereas SICF was comparable between interventions (all P > .10). For the active intervention, responses did not vary between PA and AP iTMS (Experiment 2, all P > .14), and muscle activation reduced the effect of AP iTMS during the intervention (Experiment 3, P = .002). Coil orientation influenced the MEP response after iTMS, and muscle activation reduced the response during iTMS. While this suggests that AP iTMS may be beneficial in producing a neuroplastic modulation of I-wave circuits in resting muscle, further exploration of factors such as dosing is required.

14-3-3ζ Plays a key role in the modulation of neuroplasticity underlying the antidepressant-like effects of Zhi-Zi-Chi-Tang

BackgroundZhi-Zi-Chi-Tang (ZZCT) is an effective traditional Chinese medicinal formula. ZZCT has been used for the treatment of depression for centuries. Its clinical efficacy in relieving depression has been confirmed. However, the molecular mechanisms of ZZCT regarding neuroplasticity in the pathogenesis of depression have not yet been elucidated. PurposeThe present study aimed to examine the effects of ZZCT on neuroplasticity in mice exposed to chronic unpredictable mild stress (CUMS), and to explore the underlying molecular mechanisms. MethodsFor this purpose, a murine model of depression was established using the CUMS procedure. Following the intragastric administration of ZZCT or fluoxetine, classic behavioral experiments were performed to observe the efficacy of ZZCT as an antidepressant. Immunofluorescence was used to label and quantify microtubule-associated protein (MAP2) and postsynaptic density protein (PSD95) in the hippocampus. Golgi staining was applied to visualize the dendritic spine density of neurons in the hippocampi. Isolated hippocampal slices were prepared to induce long-term potentiation (LTP) in the CA1 area. The hippocampal protein expression levels of glycogen synthase kinase-3β (GSK-3β), p-GSK-3β (Ser9), cAMP response element binding protein (CREB), p-CREB (Ser133), brain-derived neurotrophic factor (BDNF) and 14–3–3ζ were detected using western blot analysis. The interaction of 14–3–3ζ and p-GSK-3β (Ser9) was examined using co-immunoprecipitation. LV-shRNA was used to knockdown 14–3–3ζ by an intracerebroventricular injection. ResultsZZCT (6 g/kg) and fluoxetine (20 mg/kg) alleviated depressive-like behavior, restored hippocampal MAP2+ PSD95+ intensity, and reversed the dendritic spine density of hippocampal neurons and LTP in the CA1 region of mice exposed to CUMS. Both low and high doses of ZZCT (3 and 6 g/kg) significantly promoted the binding of 14–3–3ζ to p-GSK-3β (Ser9) in the hippocampus, and ZZCT (6 g/kg) significantly promoted the phosphorylation of GSK-3β Ser9 and CREB Ser133 in the hippocampus. ZZCT (3 and 6 g/kg) upregulated hippocampal BDNF expression in mice exposed to CUMS. LV-sh14–3–3ξ reduced the antidepressant effects of ZZCT. ConclusionZZCT exerted antidepressant effects against CUMS-stimulated depressive-like behavior mice. The knockdown of 14–3–3ζ using lentivirus confirmed that 14–3–3ζ was involved in the ZZCT-mediated antidepressant effects through GSK-3β/CREB/BDNF signaling. On the whole, these results suggest that the antidepressant effects of ZZCT are attributed to restoring damage by neuroplasticity enhancement via the 14–3–3ζ/GSK-3β/CREB/BDNF signaling pathway.

The factors affecting neurogenesis after stroke and the role of acupuncture.

Stroke induces a state of neuroplasticity in the central nervous system, which can lead to neurogenesis phenomena such as axonal growth and synapse formation, thus affecting stroke outcomes. The brain has a limited ability to repair ischemic damage and requires a favorable microenvironment. Acupuncture is considered a feasible and effective neural regulation strategy to improve functional recovery following stroke via the benign modulation of neuroplasticity. Therefore, we summarized the current research progress on the key factors and signaling pathways affecting neurogenesis, and we also briefly reviewed the research progress of acupuncture to improve functional recovery after stroke by promoting neurogenesis. This study aims to provide new therapeutic perspectives and strategies for the recovery of motor function after stroke based on neurogenesis.

An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome.

We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.

Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders.

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.

Ketamine May Exert Rapid Antidepressant Effects Through Modulation of Neuroplasticity, Autophagy, and Ferroptosis in the Habenular Nucleus

Major depressive disorder is a burdensome condition with few treatment options, and traditional antidepressants are characterized by slow onset. Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD), the mechanisms of which remain elusive. In this study, we explored whether neuroplasticity, autophagy, and ferroptosis in the habenular nucleus are involved in the rapid antidepressant process of ketamine. The results showed that Chronic Restraint Stress (CRS) treated rats exhibited decreased neuroplasticity, inhibition of autophagy, and enhanced ferroptosis. Depression-like symptoms were significantly improved after ketamine treatment in CRS rats, with changes in physiological parameters. Ketamine-treated CRS rats showed a significant improvement in habenular nuclear neuroplasticity. Electron microscopy observed that ketamine triggered autophagy, with increased levels of autophagy-related proteins. Ferroptosis was inhibited by ketamine by electron microscopy, with increased FTH1 and GPX4 levels and decreased Tfr1 levels. In conclusion, our findings demonstrate that ketamine may exert rapid antidepressant effects by improving neuroplasticity, activating autophagy, and inhibiting ferroptosis in the nuclear complex.

Evaluation of the role of lisdexamfetamine on attention-deficit/hyperactivity disorder common psychiatric comorbidities: mechanistic insights on binge eating disorder and depression

IntroductionAttention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition in which children suffer from inattentiveness, hyperactivity, and or impulsivity. ADHD patients frequently present comorbid psychiatric disorders: in adults, the most common are depression, substance-related disorders, anxiety, and eating disorders. Children and adolescents present conduct disorders, learning disorders, anxiety and depression. Since ADHD and its psychiatric comorbidities share similarities, a partial overlap of their pathophysiological mechanisms has been suggested. ADHD, can be treated with lisdexamfetamine (LDX), a prodrug indicated by the FDA as treatment for binge eating disorder (BED) and ADHD.ObjectivesTo evaluate, through a systems biology-based in silico method, the efficacy of LDX as first-line ADHD treatment to improve ADHD psychiatric comorbidities. Furthermore, we explored the molecular mechanisms behind LDX’s action.MethodsWe used the systems biology- and artificial intelligence-based Therapeutic Performance Mapping System (TPMS) technology to characterise and model ADHD comorbidities. Artificial neural networks (ANNs) algorithms were used to identify specific relationships between protein sets. Finally, we modelled the mechanisms of LDX for the most relevant comorbidities by using sampling methods and comorbidity-specific virtual patients in each case.ResultsThis study predicts a strong relationship between LDX’s targets and proteins involved in BED and depression (Fig 1). Our results could be explained not only by LDX role in neurotransmitter regulation, but also by modulation of neuroplasticity (BDNF/NTRK2, GSK3), neuroinflammation (interleukins, inflammasome), oxidative stress (NOS2, SOD), and the hypothalamic-pituitary-adrenal (HPA) axis (CRH, CRHR1).ConclusionsThese findings could be used in pre-clinical and clinical future investigations to assess optimal treatment for ADHD patients with psychiatric comorbidities.DisclosureJRGC: speaker for Takeda and Shire, research funding from Shire and Lumbeck, collaborations with Laboratoires Servier JQ: speaker or scientific advisor for Takeda, Janssen, Rubio. Investigation funding: Instituto de Salud Carlos III. PR, CM, TPR: full-ti

0263 Slow-wave Disruption Improves Irritability in Males with Major Depression: Potential Implications for Understanding the Impact of Sex Differences on Sleep and Neuroplasticity

Abstract Introduction Irritability has been proposed to be a core symptom of male-specific major depressive disorder (MDD), with a greater propensity to experiencing anger attacks and overreacting to minor annoyances compared to females with MDD. Males with MDD have also been shown to exhibit a pattern of reduced slow-wave sleep (SWS) that is not characteristic of females. Because SWS has been implicated in the homeostatic regulation of neuroplasticity, it is possible that this mood dysfunction in males is a result of SWS alterations via impairments in neuroplasticity. Therefore, in this study we aimed to manipulate SWS and examine its impact on mood. Methods 19 individuals (11 F) with MDD were recruited for an ongoing clinical trial. Participants spent two nights in the sleep laboratory one week apart: a baseline (BL) night, and a night of slow-wave sleep disruption (SWD) utilizing auditory stimulation. Irritability was assessed in the morning following each overnight visit using the 5-item Brief Irritability Test (BITe). Repeated measures ANOVA was used to evaluate the change in irritability following SWD with condition (BL, SWD) as the within-subject factor and sex (M, F) as the between-subjects factor. Results Results revealed a significant Condition x Sex interaction (F(1,17) =10.1, p=.006) for change in irritability scores, with post-hoc t-tests indicating that males with MDD showed a significant decrease in irritability following SWD, t(7)=2.22, p<.05 while women showed a significant increase in irritability, t(10)=-2.34, p<.05. Changes in irritability were not found to be associated with changes in N3. Conclusion These data demonstrate that experimentally reducing SWS decreases irritability, a core symptom of mood dysfunction, in males with MDD. As SWS has been theorized to facilitate synaptic downscaling, these results may indicate that maintaining waking levels of synaptic strength in males improves depressive symptomatology and may point to the importance of sex differences in sleep and psychopathology. Moreover, these results suggest that the modulation of neuroplasticity via sleep manipulation may be a potential therapeutic target. Support (If Any) K23MH118580 (JG)

P305. A Single Night of Slow-Wave Sleep Disruption Improves Mood and Enhances Motivation in Anhedonic Depression

Sleep deprivation results in a robust antidepressant response in 50% of individuals with major depression (MDD), with anhedonia being a strong predictor of response. Although the mechanism of this antidepressant effect is not known, one potential candidate may be via the modulation of neuroplasticity. Sleep slow-wave activity (SWA) has been suggested to facilitate the homeostatic modulation of neuroplasticity; thus, in this study we aimed to examine if selectively reducing SWA via auditory stimulation could improve mood and motivation in individuals with MDD with anhedonia.

Escitalopram modulates learning content-specific neuroplasticity of functional brain networks

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.