RESUMEN
Deep brain stimulation (DBS) significantly alleviates symptoms in various neurological disorders. Current research focuses on developing programmed stimulation protocols for customization to individual symptoms. However, the therapeutic mechanism of action of programmed DBS (pDBS) is poorly understood. We previously demonstrated that pDBS in the ventral tegmental area (VTA) normalizes molecular and behavioral abnormalities in the Flinders Sensitive Line (FSL) rat model for depression. Herein, we examined the effect of a short-duration, low-frequency DBS template on local field potential (LFP) synchronization patterns along the anterior-posterior axis of the VTA of FSL rats, and correlation of this effect with depressive-like behavior, as compared with non-programmed, continuous low-frequency DBS (npDBS). We used the wavelet phase coherence (WPC) measure for effective representation of time and frequency of LFP patterns, and the forced swim test to measure immobility (despair). Baseline WPC values were lower in FSLs as compared with SD controls, at the low and high gamma frequency range (above 30 Hz). Baseline immobility scores for FSL rats were higher than those of SD rats, while pDBS, and not npDBS, significantly reduced FSL immobility scores to control SD levels, up to day 14. pDBS also significantly increased the change (between baseline and day 14) in WPC values, in beta, low gamma and high gamma frequency ranges. The change in high gamma (60-100 Hz) WPC values correlated with improvement in depressive-like behavior. Our results suggest that programmed DBS of the VTA increases interaction among local neuronal populations, an effect that may underlie the normalization of depressive-like behavior.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Depresión/fisiopatología , Depresión/terapia , Ritmo Gamma , Área Tegmental Ventral/fisiopatología , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Posttraumatic stress disorder (PTSD) is a severe, persistent psychiatric disorder in response to a traumatic event, causing intense anxiety and fear. These responses may increase over time upon conditioning with fear-associated cues, a phenomenon termed fear incubation. Corticotropin-releasing factor receptor type 1 (CRFR1) is involved in activation of the central stress response, while corticotropin-releasing factor receptor type 2 (CRFR2) has been suggested to mediate termination of this response. Corticotropin-releasing factor (CRF) receptors are found in stress-related regions, including the bed nucleus of stria terminalis (BNST), which is implicated in sustained fear. METHODS: Fear-related behaviors were analyzed in rats exposed to predator-associated cues, a model of psychological trauma, over 10 weeks. Rats were classified as susceptible (PTSD-like) or resilient. Expression levels of CRF receptors were measured in the amygdala nuclei and BNST of the two groups. In addition, lentiviruses overexpressing CRFR2 were injected into the medial division, posterointermediate part of the BNST (BSTMPI) of susceptible and resilient rats and response to stress cues was measured. RESULTS: We found that exposure to stress and stress-associated cues induced a progressive increase in fear response of susceptible rats. The behavioral manifestations of these rats were correlated both with sustained elevation in CRFR1 expression and long-term downregulation in CRFR2 expression in the BSTMPI. Intra-BSTMPI injection of CRFR2 overexpressing lentiviruses attenuated behavioral impairments of susceptible rats. CONCLUSIONS: These results implicate the BNST CRF receptors in the mechanism of coping with stress. Our findings suggest increase of CRFR2 levels as a new approach for understanding stress-related atypical psychiatric syndromes such as PTSD.