Cognitive neurobehavior and synaptic plasticity after vagus nerve stimulation in female rats: Interaction between estrous cycle and neurostimulation

A single session of vagus nerve stimulation (VNS) has been shown to improve cognition in male rodents, but the influence of sex on the effects of VNS on behavior and synaptic plasticity are poorly understood. The present study investigated cognitive performance and hippocampal (HC) electrophysiology/brain derived neurotrophic factor (BDNF) expression in female healthy adult rats to examine changes in cognition and synaptic plasticity after VNS paired training. A total of 44 female rats were utilized for the cognitive neurobehavior experiments and a total of 68 female rats were utilized for the electrophysiology experiments. Animals were divided into four groups: SHAM in diestrus (SHAM-D), SHAM in estrus (SHAM-E), VNS in diestrus (VNS-D), and VNS in estrus (VNS-E). Electrode wires were surgically implanted around the left cervical vagus nerve (VN) prior to stimulation and experimentation in female Sprague–Dawley rats. A single 30 min session of VNS (100 µs biphasic pulses, 30 Hz, 0.8 mA) was administered after neurobehavior training in a Novel Object Recognition (NOR) and a Passive Avoidance Task (PAT) and testing was performed 24 h after VNS. Electrophysiology recordings for input/output, long-term potentiation, spontaneous spiking, and paired-pulse facilitation (PPF) were collected 90 min after VNS to assess the functional effects of VNS on HC slices. Immunohistochemistry (IHC) was conducted on HC slices collected 48 h after VNS to quantify HC subregion specific changes in BDNF. Stimulated rats exhibited improved performance in the PAT when tested in the diestrus phase. Among all subjects, VNS increased response amplitude and decreased PPF. However, among those in diestrus VNS increased long-term potentiation (LTP) amplitude and frequency of spontaneous spiking, and decreased PPF in the CA1. Among those in estrus, VNS did not change LTP amplitude or PPF, but frequency of spontaneous spiking was increased. VNS and estrous cycle stage additionally influenced the HC expression of BDNF in the CA1 and CA2. These findings suggest that a single session of VNS can increase synaptic plasticity, but that an interaction between estrous cycle phase and VNS influences the effects of VNS in females. This study is among the first to investigate the influence of estrous cycle phase on cognitive neurobehavior and synaptic plasticity outcomes after VNS and contributes to the understanding of VNS-induced cognitive enhancement.