Brain plasticity enables adaptive learning, memory, and behavior, yet it is neither unconstrained nor automatic. Emerging evidence indicates that synaptic change occurs within a hierarchy of interacting regulatory layers that collectively determine when, where, and how plasticity is expressed. We propose a four-layer hierarchical framework in which plasticity is shaped by energetic constraints, homeostatic stability, neuromodulatory gating, and experience-dependent synaptic modification. Energetic limits set metabolic boundaries for synaptic change, while homeostatic mechanisms maintain network excitability and excitation-inhibition balance. Neuromodulators, including dopamine, acetylcholine, noradrenaline, and serotonin, dynamically gate plasticity based on behavioral relevance, salience, and internal state. Finally, Hebbian and spike-timing-dependent mechanisms implement input-specific synaptic modifications that encode adaptive information. Dysregulation at any of these layers is proposed to contribute to clinical deficits: insufficient gating impairs learning and motivation, excessive or shifted gating balance stabilizes maladaptive circuits or distorts salience, and reduced consistency in gating dynamics undermines attention and flexibility. This perspective reframes neurological and psychiatric disorders as conditions of controlled plasticity failure (i.e., failure of one or more regulatory layers to appropriately permit or restrict synaptic change) rather than simple neurotransmitter imbalances. By integrating metabolic, cellular, circuit, and behavioral dimensions, our framework provides a mechanistic understanding of adaptive and maladaptive plasticity, offering principles to guide therapeutic interventions that restore context-appropriate learning and cognitive function.
A quantitative description of the adenosine and caffeine influence on the glutamatergic synaptic neurotransmission is presented. The analysis is based on a set of coupled mathematical models for a sequence of processes involved in the synaptic transmission, starting from the action potential at the presynaptic axonal terminal and up to the spike generation at the postsynaptic membrane. Adenosine and caffeine act via binding to the presynaptic adenosine receptors that results in the alteration of axon terminal calcium ion influx and, thereby, in the modulation of the efficiency of neurotransmitter release. Dynamics of the glutamate in the synaptic cleft were determined taking into account its release from the presynaptic vesicles with subsequent glutamate diffusion and reuptake. Maximal value of the glutamate concentration in the cleft is about 1.2 mM. The glutamate content elevation induces a spike at the postsynaptic neuron. The dependence of the synaptic transmission efficiency on the levels of adenosine and caffeine has been analyzed. The probability of the synaptic transmission is increased from 0.3 to about 0.5 when varying caffeine concentration from 0 to 200 µM. Transmission probability significantly depends on the number of the postsynaptic glutamate receptors.
Though the nucleus accumbens (NAc) is a key terminal region of the mesolimbic dopaminergic system, it is also innervated by noradrenergic inputs from the ventral medulla and contains intrinsic cholinergic neurons. However, the roles of α-adrenoceptors in regulating basal accumbal cholinergic activity remain unclear. This study employed in vivo microdialysis in unanesthetized rats to investigate the role of α1- and α2-adrenoceptors in modulating extracellular acetylcholine (ACh) levels in the NAc. Accumbal administration of the α2-agonist UK 14304 (30.0 and 300.0 pmol) and the α2-antagonist RX 821002 (0.6, 600.0, and 6000.0 pmol) dose-dependently decreased and increased accumbal ACh efflux, respectively. Neither compound (UK 14304: 300.0 pmol; RX 821002: 6000.0 pmol) affected basal accumbal dopamine levels. Co-administration of RX 821002 (0.6 pmol) blocked the UK 14304 (300.0 pmol)-induced reduction in ACh efflux, whereas UK 14304 (30.0 pmol) inhibited the RX 821002 (6000.0 pmol)-induced increase. Intraperitoneal administration of RX 821002 (1.0 mg/kg), but not UK 14304 (2.5 mg/kg), increased accumbal ACh efflux, which was inhibited by intra-accumbal infusion of UK 14304 (30.0 pmol). Neither the α1-agonist methoxamine (0.24 pmol) nor the α1-antagonist prazosin (6.0 pmol) altered accumbal ACh levels. Doses of drugs infused indicate the total amount (mol) during the 60-min infusion. These findings indicate that RX 821002 enhances ACh efflux in the NAc by blocking accumbal α2-adrenoceptor-mediated inhibition of ACh release. Given that reduced accumbal ACh levels have been implicated in cognitive impairment, systemic administration of α2-adrenoceptor antagonists should be investigated for their potential to improve such deficits in experimental models.
This study aimed to investigate the role and underlying mechanism of lncRNA MIAT in sevoflurane (Sev)-induced cognitive dysfunction in neonatal rats, thereby offering theoretical basis for clinical intervention. Seven-day-old Sprague-Dawley (SD) rats were chosen to construct a Sev-induced cognitive dysfunction model. Anxiety-like behavior and locomotor activity were assessed by the open field test (OFT), whereas cognitive function was evaluated using novel object recognition (NOR) test and Morris water maze (MWM) test. The expression levels of lncRNA MIAT, miR-15b-5p, and Ccnd1 were detected by RT-qPCR. The dual-luciferase reporter gene assay was carried out to validate the targeted binding relationships. Sev exposure led to a downregulation of lncRNA MIAT expression in rat hippocampus. lncRNA MIAT alleviated Sev-induced cognitive impairment, as manifested by increased central zone residence time in OFT, elevated recognition index (RI) in NOR test, shortened escape latency, increased platform crossings, and prolonged target quadrant residence time in MWM test. Mechanistically, lncRNA MIAT directly targeted miR-15b-5p and inhibited its expression. miR-15b-5p targeted Ccnd1 and suppressed its expression. Overexpression of miR-15b-5p or silencing of Ccnd1 reversed the neuroprotective effect of lncRNA MIAT. LncRNA MIAT ameliorates Sev-induced cognitive dysfunction in neonatal rats by sponging miR-15b-5p to upregulate Ccnd1 expression, which may serve as a potential target for preventing Sev-related neurotoxicity.
A complete human sleep consists of multiple states, each of which has its own unique and typical characteristics. A clear definition of these states lays a solid foundation for the study of related sleep disorders. However, there remain significant challenges in current research on human sleep. Focusing on the automatic staging of sleep states, this review is organized around the technical route, technical challenges, and future perspectives of sleep staging. First, 2044 records related to sleep staging were initially screened from the Web of Science Core Collection, and key methodological themes were identified through an initial screening. Second, more than 200 highly relevant studies were selected for review, and 174 of them were cited. Compared with previous surveys on automated sleep staging, in this paper, more attention is paid to the complete technical route, key technical challenges, data strategy, and future research trends. Special attention is given to the N1 stage, which represents the most challenging classification target due to both its inherent physiological ambiguity and low inter-scorer reliability under the current AASM framework. This review aims to provide a practically oriented and operationally actionable reference for researchers in the field.
