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<p>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<sup>+</sup> current <InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(({I}_{AHP})\)</EquationSource> </InlineEquation> blocked by HA, and the anomalous rectifier current <InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(({I}_{h})\)</EquationSource> </InlineEquation> activated by HA. The HA-TNMM is further formulated by adding <InlineEquation ID="IEq3"> <EquationSource Format="TEX">\({I}_{AHP}\)</EquationSource> </InlineEquation> and <InlineEquation ID="IEq4"> <EquationSource Format="TEX">\({I}_{h}\)</EquationSource> </InlineEquation> 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 <InlineEquation ID="IEq5"> <EquationSource Format="TEX">\({I}_{AHP}\)</EquationSource> </InlineEquation>, allowing <InlineEquation ID="IEq6"> <EquationSource Format="TEX">\({I}_{AHP}\)</EquationSource> </InlineEquation> to increase; the enhanc <InlineEquation ID="IEq7"> <EquationSource Format="TEX">\({I}_{AHP}\)</EquationSource> </InlineEquation> 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 <InlineEquation ID="IEq8"> <EquationSource Format="TEX">\({I}_{h}\)</EquationSource> </InlineEquation>, 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.</p>

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Histamine regulation in shaping spindle refractoriness: a computational modeling study

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Bo Wang,
  • Qiang Li,
  • Wen-Hua Wang,
  • Wan-Rong Zan,
  • Yi-Ming Li,
  • Jiang-Ling Song,
  • Rui Zhang

摘要

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 \(({I}_{AHP})\) blocked by HA, and the anomalous rectifier current \(({I}_{h})\) activated by HA. The HA-TNMM is further formulated by adding \({I}_{AHP}\) and \({I}_{h}\) 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 \({I}_{AHP}\) , allowing \({I}_{AHP}\) to increase; the enhanc \({I}_{AHP}\) 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 \({I}_{h}\) , 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.