RESUMO
PTSD is heterogeneous disorder that can be long lasting and often has delayed onset following exposure to a traumatic event. Therefore, it is important to take a staging approach to evaluate progression of biological mechanisms of the disease. Here, we begin to evaluate the temporal trajectory of changes following exposure to traumatic stressors in the SPS rat PTSD model. The percent of animals displaying severe anxiety on EPM increased from 17.5% at one week to 57.1% two weeks after SPS stressors, indicating delayed onset or progressive worsening of the symptoms. The LC displayed prolonged activation, and dysbalance of the CRH/NPY systems, with enhanced CRHR1 gene expression, coupled with reduced mRNAs for NPY and Y2R. In the mediobasal hypothalamus, increased CRH mRNA levels were sustained, but there was a flip in alterations of HPA regulatory molecules, GR and FKBP5 and Y5 receptor at two weeks compared to one week. Two weeks after SPS, intranasal NPY at 300 µg/rat, but not 150 µg which was effective after one week, reversed SPS triggered elevated anxiety. It also reversed SPS elicited depressive/despair symptoms and hyperarousal. Overall, the results reveal time-dependent progression in development of anxiety symptoms and molecular impairments in gene expression for CRH and NPY systems in LC and mediobasal hypothalamus by SPS. With longer time afterwards only a higher dose of NPY was effective in reversing behavioral impairments triggered by SPS, indicating that therapeutic approaches should be adjusted according to the degree of biological progression of the disorder.
Assuntos
Expressão Gênica , Hipotálamo/metabolismo , Locus Cerúleo/metabolismo , Neuropeptídeo Y/farmacologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/biossíntese , Masculino , Neuropeptídeo Y/biossíntese , Ratos , Receptores de Hormônio Liberador da Corticotropina/biossíntese , Receptores de Neuropeptídeo Y/biossíntese , Proteínas de Ligação a Tacrolimo/biossíntese , Fatores de TempoRESUMO
Fasting-induced LH suppression is augmented by estrogen in female rats. We investigated the temporal changes in the number of estrogen receptor alpha (ERalpha)-immunoreactive (ir) cells in various brain regions in ovariectomized rats fasted for 6, 24, 30, and 48 h, commencing at 1300 h. We also determined the anatomical relationship of ERalpha immunoreactivity and dopamine-beta-hydroxylase (DBH) neurons in the A2 region of the nucleus of the solitary tract (NTS) and the paraventricular nucleus (PVN). The number of ERalpha-ir cells significantly increased after 30 h from the onset of fasting in the PVN and NTS compared with the unfasted controls and was sustained until 48 h. In the A2 region of 48-h fasted rats, 46.75% DBH-ir cells expressed ERalpha, and this was significantly higher than in unfasted controls (8.16% DBH-ir cells expressed ERalpha). In the PVN, most ERalpha-ir neurons were juxtaposed with DBH-ir varicosities. These results suggest that ERalpha is expressed in specific brain regions at a defined time from the onset of fasting. In addition, the anatomical relationship of noradrenergic and ERalpha-ir neurons in the A2 region and PVN may suggest a role for estrogen in increasing the activity of noradrenergic neurons in the A2 region and enhancing sensitivity of the PVN to noradrenergic input arising from the lower brainstem and thereby augmenting the suppression of LH secretion during fasting.