Alzheimer’s disease (AD), the most common form of dementia, is characterized by cholinergic dysfunction and early impairments in episodic and recognition memory. Although retrieval failure represents a hallmark of cognitive decline in AD, the task- and phase-specific molecular mechanisms underlying cholinergic-dependent memory retrieval remain poorly defined. This study investigated whether acute muscarinic cholinergic blockade disrupts the retrieval phase of recognition memory. We also examined the associated regulation of hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII) isoforms α and β, together with extracellular signal-regulated kinase (ERK) signaling. Adult male SWR/J mice were trained in the NOR paradigm and administered scopolamine (1 mg/kg, i.p.) or saline 30 min prior to the retrieval phase. Recognition memory performance was assessed using the discrimination index and exploratory preference. Immediately following behavioral testing, hippocampal tissue was collected for Western blot analysis of phosphorylated and total CaMKII-α, CaMKII-β, and ERK. Scopolamine significantly impaired recognition memory retrieval, as evidenced by a reduced discrimination index and decreased preference for the novel object, without diminishing overall exploratory activity. At the molecular level, scopolamine-induced cholinergic inhibition selectively decreased hippocampal phosphorylation of both CaMKII-α and CaMKII-β while increasing ERK phosphorylation, with no significant changes in total protein expression of any kinase. These findings identify a retrieval-specific, scopolamine-induced molecular signature of cholinergic inhibition in the hippocampus, characterized by concurrent suppression of both CaMKII isoform activities (α and β) alongside dissociable ERK hyperactivation. By extending prior molecular observations from aversively motivated paradigms to an ethologically relevant model of recognition memory, this study provides mechanistic insight into how cholinergic dysfunction contributes to memory retrieval deficits and suggests that cholinergic signaling maintains the functional (CaMKII-α) and structural (CaMKII-β) dimensions of hippocampal memory retrieval machinery through coordinated kinase activation.
Aberrant protein phosphorylation and sustained neuroinflammatory activation are key biochemical features of experimental parkinsonism. Dysregulated tau processing and excessive microglial reactivity have been implicated in motor dysfunction associated with dopaminergic injury. In the present study, we evaluated the biochemical and functional effects of Leucettine L41 using biochemical, cellular, and in vivo systems. In an in vitro tau aggregation assay, L41 reduced the ThT fluorescence, indicating the suppression of fibril formation. In SH-SY5Y neuronal cells, L41 decreased tau phosphorylation at the Ser202/Thr205 site. In lipopolysaccharide-stimulated BV-2 microglial cells, L41 suppressed the production of nitric oxide, TNF-α, IL-1β, and IL-6, demonstrating its anti-inflammatory activity. Notably, L41 did not prevent toxin-induced neuronal cytotoxicity, suggesting that its primary action may not involve direct neuroprotection. In an MPTP-induced mouse model of Parkinson’s disease, systemic L41 administration improved motor performance, accompanied by reduced tau phosphorylation and attenuated microglial activation in brain tissue. These findings indicate that L41 modulates tau aggregation, phosphorylation, and neuroinflammatory signaling in experimental parkinsonism, in association with functional motor improvement.
Intracerebral hemorrhage (ICH) is a health challenge resulting in death or disability. Iron overload has been identified as one of post-ICH damaging factors. However, the impact of iron overload, as well as the underlying mechanisms, on neural stem/progenitor cells (NSPCs) remains unknown. In this study, we found that iron overload induced significant NSPC death in a dose-dependent manner. Interestingly, iron overload increased the number of early and late apoptotic cells and the expression of caspase-3 in NSPCs. Moreover, iron overload was highly correlated with enhanced intracellular reactive oxygen species (ROS) generation and loss of mitochondrial integrity. Further, iron overload activated mTOR signaling and downregulated AMP-activated protein kinase (AMPK) phosphorylation. Importantly, drugs that eliminate ROS or activate AMPK prevented this event, as well as apoptosis of NSPCs. These results indicate that post-ICH iron overload in the brain induces excessive ROS generation and leads to NSPC death by regulating mTOR and AMPK signaling.
Extensive research with rodent models has shown detrimental effects of early-life adversity (ELA) on behavioral (e.g., impulsive behavior, anxiety, and depression) and neurobiological processes (e.g., alterations of neuroendocrine processes and maturation of brain areas). However, heterogeneous methodologies, including types and variations of ELA manipulations could have contributed to inconsistent findings across studies. Recent research indicates that the combination of the two most widely implemented rodent ELA protocols, Maternal Separation (MS) and Limited Bedding/Nesting (LBN), produces consistent and robust behavioral effects. We assessed the effects of combined MS-LBN on four processes linked to both ELA and behavioral disorders in later stages of life: incentive salience of reward cues, and impulsive choice, action, and persistence/perseverance. Sixteen male Sprague Dawley rats were divided in groups of combined MS-LBN during postnatal days 2–21 and without ELA. They were exposed to an Autoshaping Pavlovian conditioning task (AUT), a delay-discounting task (DDT), and acquisition and extinction of a multiple schedule of reinforcement with long and short Variable Intervals (VI) across a span of 18 weeks. Compared to the No-ELA group, ELA rats displayed higher goal-tracking during the AUT (higher nose-poking in the food-delivery location), higher impulsive choice during test and 7-week re-test of the DDT (preference for the smaller-sooner reinforcer over the larger-later), and less efficient responding during the long-interval schedule of reinforcement (more unnecessary responses per pellet). Associations between autoshaping and reinforcement-schedule performance were identified, with ELA moderating the relationship between sign tracking and efficiency during training and persistence/perseverance during extinction. Combined MS-LBN was associated with task-specific changes in reward-related and impulsive behavior in male rats. These complex patterns of disruptions across behavioral processes adds further support to the notion that combined ELA protocols are promising robust models of adverse rearing in humans, which often entails multiple stressors. Not applicable.
Cisplatin-induced neurotoxicity is driven in part by neuroinflammation and oxidative injury in vulnerable brain regions. Glycine has anti-inflammatory and antioxidant properties that may offer neuroprotection against chemotherapy-related brain damage. Twenty-five adult male BALB/c mice were randomized into five groups (n = 5/group) Group 1 received cisplatin for 14 days; Group 2 received cisplatin plus glycine for 14 days; Group 3 received cisplatin for 28 days; Group 4 received cisplatin for 14 days followed by glycine for 14 days; and Group 5 received cisplatin for 28 days with glycine introduced from day 14 to day 28. Cisplatin was administered intraperitoneally at 3 mg/kg every fourth day, and glycine was given subcutaneously at 1 g/kg daily. The primary outcome was serum TNF-α measured by ELISA. Secondary outcomes were neuronal integrity and optical density in the hippocampus and frontal cortex assessed by Nissl staining. Data were analyzed using one-way ANOVA with Tukey post-hoc testing. Serum TNF-α levels differed significantly among groups (F = 230.422, p < 0.001). Mean TNF-α concentrations were 150.0 pg/mL in Group 1, 130.2 pg/mL in Group 2, 201.4 pg/mL in Group 3, 159.4 pg/mL in Group 4, and 171.0 pg/mL in Group 5. Prolonged cisplatin exposure (Group 3) produced the highest TNF-α levels, whereas concurrent glycine administration during the 14-day regimen (Group 2) resulted in the lowest levels. Compared with the 28-day cisplatin group, both delayed glycine treatment (Group 4) and glycine introduced during the second half of cisplatin exposure (Group 5) were associated with lower TNF-α concentrations. Histological analysis demonstrated reduced Nissl staining intensity and neuronal preservation in cisplatin-only groups, particularly Group 3, whereas glycine-treated groups showed better preservation of neuronal architecture and optical density in the hippocampus and frontal cortex. Glycine attenuated cisplatin-induced neuroinflammation and preserved neuronal integrity in the hippocampus and frontal cortex of mice. These findings support further preclinical evaluation of glycine as a low-cost adjuvant strategy to reduce chemotherapy-associated neurotoxicity.
