关键词: 丘脑-皮质环路, 丘脑网状核, 感觉门控, gamma振荡

Abstract: Sensory gating, the brain's protective mechanism to filter irrelevant stimuli, is profoundly impaired in schizophrenia (SCZ), leading to cognitive overload and severe cognitive deficits. While the phenomenon has been extensively studied at the behavioral and electrophysiological levels, the precise circuit-level mechanisms, particularly how the thalamocortical system orchestrates this filtering process, remain incompletely understood. This review advances a comprehensive theoretical framework that integrates three interacting levels of thalamocortical organization: (1) feedforward inhibitory pathways from the thalamus to the prefrontal cortex, (2) inhibitory gating by the thalamic reticular nucleus (TRN) onto thalamic relay nuclei, and (3) top-down corticothalamic feedback that dynamically switches thalamic firing modes according to attentional states.
First, we propose a dual-inhibition mechanism mediated by the TRN. We hypothesize that glutamatergic neurons in the auditory cortex excite GABAergic neurons within the TRN. These TRN GABAergic neurons subsequently execute a dual regulatory function: (1) they inhibit the medial geniculate nucleus (MGB), effectively blocking subsequent auditory interference and protecting ongoing auditory processing in the cortex; (2) they inhibit excitatory neurons in higher-order thalamic nuclei. This inhibition induces hyperpolarization and de-inactivates T-type calcium channels. Upon the arrival of a subsequent stimulus, these channels trigger rebound burst firing, a specific thalamic firing mode that acts as a critical filter against redundant stimuli.
Second, we elucidate a thalamocortical feedforward inhibitory loop engaged during attentional states. Thalamic excitatory neurons project to and activate parvalbumin-positive (PV+) GABAergic interneurons in layer L2/3 of the prefrontal cortex (PFC). This feedforward activation promotes synchronous gamma oscillations in the medial PFC, establishing a rapid executive pathway that suppresses responses to subsequent stimuli within a narrow temporal window.
Third, we integrate a state-dependent top-down corticothalamic feedback mechanism. We theorize that attention dynamically modulates sensory gating by switching thalamic firing modes. During focused attention, high-frequency cortical activity directly excites thalamic relay neurons, maintaining tonic firing for precise information transfer. Conversely, during rest or inattention, low-frequency cortical activity indirectly inhibits the thalamus via the TRN. This hyperpolarization primes the T-type calcium channels, lowering the threshold for burst firing. When a salient stimulus occurs, it triggers a “wake-up call” burst discharge, rapidly capturing attention and enhancing the subsequent prepulse inhibition. Unlike traditional views that consider burst firing primarily a sleep or anesthesia-related epiphenomenon, we propose that, in the awake state, burst discharges serve a critical gating function: they act as a “reset” or “veto” signal that attenuates responses to closely following stimuli. This is mechanistically grounded in the low-threshold T-type calcium channels abundantly expressed in thalamic relay neurons. When TRN GABAergic neurons, activated by the first stimulus, induce hyperpolarization in higher-order thalamic excitatory neurons, these channels undergo de-inactivation. Upon subsequent depolarization, a low-threshold calcium spike triggers a high-frequency burst of sodium action potentials. We hypothesize that this rebound burst, rather than facilitating transmission, actively suppresses the second stimulus by recruiting fast feedforward inhibition in the prefrontal cortex, thereby implementing forward suppression.
At the molecular and network levels, we highlight that the hypofunction of N-methyl-D-aspartate (NMDA) and GABA receptors is the core driver of sensory gating deficits in SCZ. NMDA receptor hypofunction on PV+ interneurons leads to cortical and thalamic disinhibition, severely disrupting the excitation/inhibition (E/I) balance. This E/I imbalance directly corrupts the generation and synchronization of gamma oscillations (30-80 Hz), which are essential for local circuit communication and sensory binding. Specifically, SCZ is characterized by aberrant spontaneous gamma hyper-synchrony and diminished stimulus-evoked gamma power. Furthermore, the disrupted E/I balance impairs cross-frequency coupling (e.g., theta-gamma and alpha-gamma coupling), compromising the top-down attentional control required to filter out irrelevant sensory inputs. Consequently, the thalamocortical circuit probably fails to maintain the signal-to-noise ratio necessary for effective sensory gating, manifesting as sensory gating deficits.
In conclusion, this review presents a theoretical framework that systematically integrates the dual firing modes of the thalamus, the TRN-mediated lateral and feedforward inhibition, and the top-down corticothalamic feedback loops. By delineating how these mechanisms operate in both non-attentional and attentional states, we provide a unifying neurobiological explanation for sensory gating deficits in schizophrenia. Future research should leverage cross-species paradigms, combining optogenetics, chemogenetics, and multi-modal neuroimaging, to causally validate the dynamic switching of thalamic firing modes and the precise role of TRN subnetworks in awake behaving animals.

Key words: thalamocortical circuits, thalamic reticular nucleus, sensory gating, gamma oscillation