Differential modulation of contextual fear conditioning by orexin receptors in the dorsal hippocampus.

The dorsal hippocampus (DH) encodes contextual memories essential for adaptive responses to environmental threats. The lateral hypothalamus (LH), a primary source of orexinergic neurons in the brain, is also involved in the modulation of defensive behaviors. Although recent research links the orexinergic system to emotional processes, its role in the DH during the organization and expression of learned fear responses remains poorly understood. This study investigates the role of orexin receptor subtypes in DH during contextual fear conditioning. Anatomical tracing techniques revealed a direct projection from the lateral hypothalamus to the DH, providing evidence for a previously unexplored pathway in fear processing. Pharmacological blockade of orexin receptor type 1 (Orx1R) in the DH impaired the acquisition of contextual fear memories, while blockade of orexin receptor type 2 (Orx2R) enhanced memory formation, suggesting opposing roles for these receptors in early memory processing stages. Notably, blocking either receptor before testing did not affect the expression of pre-established fear memories, suggesting that hippocampal orexin receptors are primarily involved in memory formation rather than the expression of learned fear. These findings provide insights into the contribution of the orexinergic system to emotional learning, particularly in hippocampus-dependent fear memories. These findings advance our understanding of the orexin system, specifically the Orx1R and Orx2R functional roles, with implications for developing therapeutic strategies targeting orexin receptors in the treatment of psychiatric disorders like anxiety and post-traumatic stress disorder, which are characterized by disrupted fear processing.