Histamine regulation in shaping spindle refractoriness: a computational modeling study

The spindle refractory period refers to the interval following a spindle during which another spindle does not occur. Lengthening of the spindle refractory period (SRPL) is commonly observed in EEG recordings of patients with neuropsychiatric disorders (NPDs) and may contribute to cognitive impairments. Histamine (HA), a key neuromodulator of thalamic oscillations, has been implicated in spindle refractoriness. However, the pathways through which HA influences SRPL remain poorly understood. To address this issue, we extended the thalamic modeling framework to construct an HA-based thalamic neural mass model (HA-TNMM) incorporating HA-related neurophysiological mechanisms within a circuit composed of thalamocortical relay population (TCR) and thalamic reticular nucleus (TRN). In particular, we propose a mathematical expression to characterize the effects of HA on two critical currents: the calcium-activated K⁺ current [Formula: see text] blocked by HA, and the anomalous rectifier current [Formula: see text] activated by HA. The HA-TNMM is further formulated by adding [Formula: see text] and [Formula: see text] into Costa model. Subsequently, we investigated the model's capability to elucidate HA's effects on SRPL. Simulation results demonstrated that: (1) A decrease in HA concentration weakens HA-mediated blockade of [Formula: see text], allowing [Formula: see text] to increase; the enhanc [Formula: see text] prolongs afterhyperpolarization and thereby delays the initiation of subsequent TRN bursts, extending the inter-spindle interval and leading to SRPL; (2) An increase in HA concentration enhances [Formula: see text], raising membrane potentials, slowing spindle waning, and thus extending SRPL. Furthermore, our results were validated from a theoretical perspective. These modeling findings provide insights into the mechanisms underlying spindle refractory period modulation and offer a theoretical basis for future experimental and clinical studies.