Behavioral and Brain Functions最新文献

Cognitive functions are critical to everyday life, and enhancing cognitive abilities has significant implications for both individual development and societal advancement. However, there remains no consensus on whether cognitive capacities can be systematically improved through behavioral interventions, commonly known as cognitive training. Recent advancements in large-scale neural recordings offer unprecedented insights into the brain's cognitive mechanisms, presenting new opportunities to rigorously assess the effectiveness of cognitive training. In this review, we examine the core neural substrates underlying cognitive processes and explore generalized mechanisms of neuroplasticity associated with cognitive training. Integrating findings from animal models and human research, we emphasize the role of emerging schematic neural representations as potential mediators of cognitive transfer. Finally, we discuss future directions that could shed light on the mechanistic foundations of transfer after training, aiming to bridge the gap between experimental findings and real-world cognitive enhancement.

This study aimed to investigate the sex-dependent behavioral effects of tamoxifen, commonly used to induce Cre recombination in transgenic systems, across three developmental stages (adult, adolescent, and neonatal) and two CreERT2 mouse lines (CaMKIIα-CreERT2 and Aldh1l1-CreERT2). Both male and female mice, including wild-type C57BL/6J and CreERT2 transgenic lines, were subjected to tamoxifen treatment followed by behavioral tests assessing locomotion, anxiety-like behavior (open field test and elevated plus maze), social interaction, recognition memory (new object recognition), sucrose preference, and depression-like behavior (forced swimming test) at least 4 weeks post-treatment. We found that adult tamoxifen treatment increased depression-like behavior specifically in males, while adolescent treatment increased sucrose preference only in males, yet impaired recognition memory and increased depression-like behavior in both sexes. Neonatal treatment caused pervasive impairments, reducing locomotion and increasing anxiety- and depression-like behavior in both sexes, while enhancing social interaction only in males. Furthermore, effects differed in adult CaMKIIα-CreERT2 and Aldh1l1-CreERT2 mice. In the former, tamoxifen treatment impaired locomotion, increased anxiety-like behavior, and reduced recognition memory specifically in females, while increasing sucrose preference in males. In the latter, tamoxifen treatment impaired recognition memory in both sexes but increased sucrose preference only in males. These results demonstrate that tamoxifen alone induced long-lasting, sex-specific behavioral alterations dependent on developmental exposure. Furthermore, interactions of tamoxifen with CreERT2 expression introduced additional complexity, potentially confounding genetic studies. These findings emphasize the necessity of including appropriate controls (vehicle, tamoxifen-only, Cre-only) and both sexes in studies using the tamoxifen-inducible CreERT2-loxP system.

Background: Essential tremor (ET) is a common movement disorder characterized by persistent limb tremors. Currently, no effective treatment for ET exists. Natural plant-derived compounds, like the flavonoid, quercetin may provide therapeutic benefits, particularly when delivered in nanoemulsion formulations that enhance bioavailability and efficacy. This study evaluated the neuroprotective potential of quercetin nanoemulsion (Que-NE) in a harmaline-induced mouse model of ET.

Methods: Thirty-two male Swiss mice were randomly divided into four groups (n = 8 each): Control, Harmaline (10 mg/kg, i.p., on days 3, 5, and 7), Que-NE (20 mg/kg, i.p., for 7 days), and Harmaline + Que-NE. Harmaline was used to reliably induce tremor via olivocerebellar hyperexcitability. Behavioral performance was assessed using the open field, elevated plus maze, tail suspension, wire grip, rotarod, and passive avoidance tests. Expression of NF-κB, TNF-α, IL-1β, IL-6, NMDA receptor, and Lingo-1 was determined by RT-PCR.

Results: Que-NE significantly reduced harmaline-induced tremor severity (p < 0.0001), decreased immobility time in the tail suspension test (p = 0.0003), and improved open field anxiety-like behaviors compared with harmaline alone (P = 0.0012). Que-NE downregulated pro-inflammatory mediators (P < 0.0001) and reduced Lingo-1 gene expression (P < 0.0001). However, Que-NE showed limited efficacy in severe motor coordination tasks (rotarod, wire grip) and passive avoidance memory.

Conclusions: Que-NE exerts measurable anti-inflammatory, anxiolytic, and antidepressant-like effects in the harmaline model of ET. The impact of Que-NE on improving motor deficits, reducing inflammatory markers, and suppressing inhibitors of synaptic plasticity highlights the potential of Que-NE as a disease-modifying strategy. However, dose-response, protein-level, and long-term studies are needed to evaluate the therapeutic potential of Que-NE for ET management.

Heat Shock Protein Family A Member 1B (Hspa1b) is an RNA binding protein that regulates transcriptional and post transcriptional processes. Previous studies have suggested its protective role in stress adaptation and post injury depression, as well as its potential therapeutic effects following antidepressant treatment in major depressive disorder (MDD). However, its direct involvement in MDD remains unclear. In this study, a mouse model with hippocampal Hspa1b overexpression was established. Integrated RNA immunoprecipitation sequencing (RIP seq) and RNA sequencing (RNA seq) were performed to investigate Hspa1b mediated transcriptional regulation and alternative splicing. Overexpression of Hspa1b resulted in 401 differentially expressed genes (DEGs), including downregulation of several neuroinflammatory genes such as Lcn2, Ccl5, and Cd52, upregulation of oxytocin/neurophysin I prepropeptide (Oxt), and downregulation of intercellular adhesion molecule 1 (Icam1), which are all associated with depression pathogenesis. In addition, 1,397 significantly altered Hspa1b regulated alternative splicing events were identified. RT qPCR confirmed splicing changes in six genes, including Spata13 and Ptpro, among others linked to depression and neuronal functions. These findings demonstrate that hippocampal Hspa1b overexpression is associated with transcriptional and splicing alterations in genes related to immune, neuronal, and HPA axis pathways, which are key mechanisms implicated in MDD. Based on these alterations, Hspa1b may act as a double-edged regulator in MDD, warranting further investigation of its causal role and therapeutic potential.

Research into memory mechanisms has predominantly centered on adult male rodents, often overlooking the influences of sex and developmental stage. Memory processes vary significantly between juveniles and adults, with sex acting as a critical determinant. Oxytocin (OXT) has emerged as a key modulator of fear responses and extinction in a sex-dependent manner, with prepubertal females displaying OXT-dependent contextual extinction patterns akin to adult males. These differences likely stem from diverse trajectories of hippocampal and prefrontal cortex maturation. This study examines the CA1 region's involvement in object location memory (OLM), social recognition memory (SRM), and synaptic plasticity among juvenile male and female rats, focusing on OXT's role. Results reveal that, in juvenile (postnatal day -PND 27) protein synthesis inhibition or OXT receptor blockade with OXT receptor antagonist (OXTR-Ant) in CA1 impairs OLM and impairs long-term potentiation (LTP) uniquely in males. These findings correlate with a greater increase in CA1 c-Fos expression following OLM in juvenile males compared to females. The SRM impairment was uniform across sexes under these treatments. In adults (PND 69), OXTR-Ant caused OLM impairment solely in females. These findings underscore pronounced sex- and age-specific variations in CA1-dependent memory and synaptic plasticity, shedding light on distinct neurobiological mechanisms that emerge pre-puberty and evolve throughout development.

Cognitive flexibility-the ability to adaptively shift between different mental processes-is essential for human functioning. This meta-analysis examines age-related changes in neural correlates of cognitive flexibility using two common assessments: the Wisconsin Card Sorting Test (rule-discovery) and Task-Switching Paradigm (rule-retrieval). We synthesized findings from 85 articles comprising 118 experiments with 2246 participants across young, middle-age, and older adult groups. Activation Likelihood Estimation analyses revealed an age-related decrease in neural involvement, particularly in posterior regions, with an anterior shift in older adults. Younger adults exhibited bilateral activation patterns while older adults showed left-dominant activity, indicating neural circuit redistribution. Rule-retrieval tasks consistently engaged left-lateralized frontoparietal regions across all age groups, with middle-age adults additionally recruiting the right cerebellum and medial frontal gyrus. For rule-discovery tasks, age-related changes were observed in bilateral frontoparietal regions, with older adults showing unique activation in the left inferior frontal gyrus. These findings highlight differential aging trajectories for rule-retrieval versus rule-discovery processes, reflecting changes in neural mechanisms with aging. Furthermore, middle-age adults recruited additional regions related to conflict monitoring, whereas older adults relied more on planning-related areas, suggesting strategy differences. Our study provides critical insights into the neural underpinnings of cognitive flexibility and its age-related changes, emphasizing the need for research on mechanisms and task-specific age trajectories.

Background: Depression involves abnormal neural oscillations. Photobiomodulation (PBM) modulates such oscillations but lacks behavioral electrophysiological mechanistic studies. We explored PBM's effects on hippocampal CA1 oscillations and phase-amplitude coupling (PAC) in a depression model.

Methods: Male C57BL/6J mice were randomly divided into saline, LPS (2 mg/kg i.p.), and LPS + PBM groups (n = 10/group for behavioral tests, n = 8/group for electrophysiology). LPS groups received lipopolysaccharide to induce neuroinflammation. The LPS + PBM group underwent 810 nm PBM (20 mW/cm², 12 min/day × 4 days) starting day 4 post-injection. Anxiety- and depression-like behaviors were assessed via open field, elevated plus-maze, and tail suspension tests. Wireless electrophysiology recorded CA1 local field potentials (LFP) during rest and behaviors. Oscillations and PAC were analyzed. Data are presented as mean ± SD; group differences were evaluated by one-way ANOVA with Bonferroni post-hoc correction and ɳ² effect sizes, with two-tailed p < 0.05 taken as statistically significant.

Results: PBM (20 mW/cm²) alleviated LPS-induced anxiety and depressive behaviors. Electrophysiologically, PBM restored resting-state δ power (LPS + PBM: 0.0499 ± 0.0282, LPS: 0.1491 ± 0.0887; p < 0.01) and enhanced δ-γ coupling (LPS + PBM: 2.049 ± 0.447, LPS: 0.230 ± 0.298; p < 0.05). During anxiety tasks, PBM suppressed γ power (LPS + PBM: 0.3709 ± 0.1569, LPS: 0.5165 ± 0.06896; p < 0.05) and strengthened δ-γ PAC (LPS + PBM: 0.741 ± 0.508 vs. LPS: 0.217 ± 0.218, p < 0.05). In depression tests, PBM normalized δ power (LPS + PBM: 0.0261 ± 0.0182, LPS: 0.1315 ± 0.0619; p < 0.001) and reduced γ power (LPS + PBM: 0.2848 ± 0.0921, LPS: 0.4067 ± 0.0892; p < 0.05). No significant PAC changes was observed during depression tasks.

Conclusion: PBM therapy ameliorates LPS-induced depression and anxiety behaviors while normalizing hippocampal CA1 oscillations and cross-frequency coupling. Its effects are state-dependent, modulating distinct frequency bands and PAC across rest and behavioral contexts, revealing potential electrophysiological therapeutic mechanisms.

Background: Major depressive disorder (MDD) is a highly prevalent psychiatric disorder and one of the leading causes of disability worldwide. Neuroinflammation is strongly implicated in the pathophysiology of MDD, suggesting that regulators of neuroinflammatory signaling are feasible therapeutic targets. The CTNND1 gene encodes a member of the armadillo protein family termed p120 (or catenin delta) that functions in cell-cell adhesion and signal transduction, including among immune cells, suggesting immunomodulatory activity.

Results: We report that systemic injection of the bacterial toxin lipopolysaccharide (LPS) induced depression-like behaviors in mice while concomitantly activating the neuroinflammatory NF-κB signaling pathway, upregulating interleukin (IL)-1β expression, and reducing p120 expression in the hippocampus. Moreover, shRNA-mediated knockdown of hippocampal p120 expression also activated the NF-κB signaling pathway, enhanced IL-1β expression, and induced the same depression-like behaviors. Similarly, both LPS treatment and p120 knockdown upregulated pNF-κB and IL-1β levels in pheochromocytoma-12 cells.

Conclusions: These findings suggest that p120 may function to prevent the development or expression of depressive symptoms by suppressing proinflammatory NF-κB-IL-1β signaling in the hippocampus. Targeting p120 may be a feasible therapeutic strategy to treat MDD.

Background: Morphine addiction is a growing problem with severe consequences. Interestingly, Insulin-like Growth Factor-1 (IGF-1), a hormone with the ability to modulate neural pathways and exert neuroprotective and regenerative properties, could emerge as a potential treatment. However, to the best of our knowledge, the role of IGF-1 in the extinction and reinstatement phases of morphine induced conditioned place preference (CPP) remains unexplored. Thus, this study aimed to investigate the behavioral and biochemical effects of intracerebroventricular (ICV) IGF-1 administration on extinction and reinstatement after morphine induced CPP and c-Fos expression in nucleus accumbens (NAc).

Methods: Rats were conditioned with morphine (5 mg/kg, subcutaneously). The study examined alterations in CPP scores after administering varying multiple doses of IGF-1 (5, 10, and 20 µg) daily during the extinction and reinstatement phases of CPP, or single 20 µg dose administration prior to the extinction or prior to the reinstatement phase. Following these procedures, c-Fos levels in the NAc were quantified using the ELISA method.

Results: The findings revealed that daily administration of IGF-1 at doses of 5, 10, and 20 µg resulted in a dose-dependent reduction in conditioning scores and shorter extinction period. Importantly, only the 20 µg attenuated morphine reinstatement significantly. Additionally, c-Fos levels, which increased following morphine exposure, were markedly reduced by IGF-1 administration across all phases.

Conclusion: This study demonstrates that IGF-1 administration could facilitates the extinction and attenuate the reinstatement of morphine-induced CPP, highlighting its potential as a therapeutic strategy in opioid addiction.

Background: Adverse psychiatric symptoms caused by cannabis are a significant concern, and Δ9-tetrahydrocannabinol (THC) has been identified as a key contributor to these symptoms. THC binds to cannabinoid type 1 receptors (CB1Rs), which are abundant in the brain and associated with cognition. The prefrontal cortex (PFC) is crucial for cognitive functions. However, the functions of CB1Rs in the PFC in cognition processes remain unclear. Here, we injected arachidonylcyclopropylamide (ACPA), a CB1Rs agonist, into the PFC of male C57BL/6J mice via the cannula and conducted cognitive tests, including the novel object recognition test and object location test (OLT).

Results: These tests assessed memory in three stages: acquisition, consolidation, and retrieval. ACPA was administered immediately before each stage, and its intra-PFC administration specifically impaired memory acquisition in the OLT. In addition, in vivo microdialysis revealed that ACPA reduced extracellular GABA levels within the PFC. Next, we produced an adeno-associated virus with a glutamic acid decarboxylase promoter and an hM3Dq-encording chemogenic activator to activate GABAergic neurons in the PFC. Subsequently, deschloroclozapine (DCZ), an hM3Dq agonist, restored the memory acquisition impaired by ACPA.

Conclusion: Our findings suggest that CB1Rs in the PFC are involved in memory acquisition through the regulation of GABA release, offering new insights into how cannabis use lead to cognitive impairment.