Abstract

Altered wiring of emotional-somatomotor, but not limbic-autonomic, circuits in rat models of depression.

I. A. KERMAN; S. M. CLINTON; P. R. BURGHARDT; N. MUZAMHINDO; N. VACHHANI; C. SHABRANG; J. BEALS; H. AKIL; S. J. WATSON
Society for Neuroscience. 2008.

Abstract

In addition to cognitive and affective disturbances, major depression is characterized by physical symptoms, including dysregulation of motor control and autonomic dysfunction. We hypothesized that such functional alterations may be due to differential organization of brain circuits that regulate these functions. To test this hypothesis, we used a virally-mediated trans-synaptic tract-tracing approach to delineate emotional-somatomotor, limbic-autonomic and somatomotor-sympathetic circuits in the rat using distinct pseudorabies virus (PRV) recombinants. Experiments were carried out in two models of depression: the Wistar-Kyoto (WKY) rat (compared to the Sprague-Dawley (SD) rat) and the Low Responder (LR) rat (compared to the High Responder (HR) rat). Behavioral studies confirmed the expression of depressive-like phenotypes in WKY and LR rats. Specifically, WKY rats exhibited significantly more immobility (91.3 ± 2.7% vs. 12.6 ± 5.5%; p < 0.01), and significantly less swimming (8.7 ± 2.7% vs. 70.8 ± 6.6%; p < 0.01) and climbing (0% vs. 16.6 ± 4.7%; p < 0.01) compared to SD controls on the forced swim test (FST). Likewise, LR rats were significantly more immobile (68.5 ± 9.3% vs. 28.6 ± 7.5%; p < 0.01) and swam significantly less (24.0 ± 4.8% vs. 52.5 ± 5.3%; p < 0.01) on the FST compared to their HR counterparts. Virally-mediated transsynaptic tract-tracing studies revealed large differences in the numbers of neurons with poly-synaptic projections to skeletal muscle, but not to the adrenal gland, in the paraventricular nucleus of the hypothalamus (PVN) in both depression models compared to their respective controls. Accordingly, SD rats contained approximately three times as many neurons with poly-synaptic projections to skeletal muscle compared to WKY rats, while similar differences were detected between HR and LR rats. There were no WKY/SD or LR/HR differences in the numbers of neurons with poly-synaptic projections to the adrenal gland, or in the numbers of neurons with collateralized poly-synaptic projections to both muscle and adrenal gland. Likewise, there were no WKY/SD or LR/HR differences in the numbers of labeled gastrocnemius motoneurons, suggesting that observed differences in the PVN were not due to disparate PRV entry into first-order neurons. Overall, these data suggest differential wiring of emotional-somatomotor circuits in two different genetic rat models of depression, which may underlie their distinct behavioral phenotypes.