Novelty triggers time-dependent theta oscillatory dynamics in cortical-hippocampal-midbrain circuitry

Rapid adaptation to novel environments is crucial for survival, and this ability is impaired in many neuropsychiatric disorders. Understanding neural adaptation to novelty exposure therefore has therapeutic implications. Here, I found that novelty induces time-dependent theta (4-12Hz) oscillatory dynamics in brain circuits including the medial prefrontal cortex (mPFC), ventral hippocampus (vHPC), and ventral tegmental area (VTA), but not dorsal hippocampus (dHPC), as mice adapt to a novel environment. Local field potential (LFP) recordings were performed while mice were freely behaving in a novel or a familiar arena for 10 min. Initially, mice exhibited increased exploratory behavior upon exposure to novelty, which gradually decreased to levels observed in mice exposed to the familiar arena. Over the same time course, the mPFC, vHPC, and VTA displayed progressively increasing theta power through novelty exposure. Additionally, theta coherence and theta phase synchrony measures demonstrated that novelty weakened the connectivity between these areas, which then gradually strengthened to the level observed in the familiar group. Conversely, mice exposed to the familiar arena showed steady and consistent behavior as well as theta dynamics in all areas. Treatment with a dopamine D1-receptor (D1R) antagonist in the vHPC disrupted neurophysiological adaptation to novelty specifically in the vHPC-mPFC and vHPC-VTA circuits, without affecting behavior. Thus, novelty induces distinct theta dynamics that are not readily dictated by behavior in the mPFC, vHPC, and VTA circuits, a process mediated by D1Rs in the vHPC. The observed time-dependent circuit dynamics in the key learning and memory circuit would provide new insights for treating neuropsychiatric disorders that often show impaired novelty processing.