Research paperGABA-induced inactivation of dorsal midline thalamic subregions has distinct effects on emotional behaviors
Introduction
The paraventricular nucleus of the thalamus (PVT) is a key node integrating information about emotion, hunger, memory, pain, and arousal and relaying output to other limbic structures influencing motor behavior [12], [24]. As this nucleus spans the anterior–posterior extent of the dorsal midline thalamus, it is typically divided into anterior (aPVT) and posterior (pPVT) subregions, which show differences in their afferent and efferent connections [11], [12]. For example, while the aPVT receives its largest input from the prelimbic cortex and hippocampal subiculum, the pPVT receives its heaviest innervation from the infralimbic and anterior insular cortices in addition to the prelimbic cortex [12]. Also, whereas the aPVT projects widely to areas such as the nucleus accumbens core and shell, hypothalamic nuclei, and regions of the amygdala, the pPVT has more restricted projections that are particularly dense to the amygdala and bed nucleus of the stria terminalis [11], [24].
Due to their connections, the subregions of the PVT are in a prime position to affect behavioral responses to arousing and stressful conditions. Recent evidence suggests that the pPVT in particular is critically involved in the expression of conditioned fear [8], [14], [19]. Additionally, through a series of microinjection studies involving this subregion, Kirouac and colleagues have shown that the excitatory neuropeptide, orexin/hypocretin (OX), inhibits locomotor activity in both a novel and familiar chamber [15], decreases exploration of a novel object and the center area of an open field [16], and reduces open arm time and entries in an elevated plus maze (EPM) [17], while blockade of OX is anxiolytic, particularly in rats previously exposed to stress [9], [17]. These results support the idea that activation of neurons in the pPVT, which has strong connections with regions involved in fear and pain, leads to a decrease in locomotor activity in association with an increase in arousal and anxiety. While similar studies of the aPVT have yet to be performed, research involving ingestive behavior shows this subregion to affect different behaviors than the pPVT. Specifically, OX promotes binge drinking of alcohol after injection in the aPVT but not the pPVT, and it stimulates intake of palatable food after injection in the pPVT but not the aPVT [2], [6]. This evidence leads us to question whether the two PVT subregions might also diverge in their control of emotional behaviors.
To investigate the respective contributions of the aPVT and pPVT to emotional behavior, the present study examined their roles in locomotor activity in a novel or familiar chamber and also in anxiety in an EPM. To do this, we temporarily inactivated each subregion through microinjection with the GABAB receptor agonist baclofen together with the GABAA receptor agonist muscimol, with both receptor classes known to exist in the PVT [4], [10]. We tested the hypothesis that inactivation of the pPVT, opposite to results with OX, would decrease anxiety while increasing locomotor activity, and inactivation of the aPVT, which has weaker connections with fear- and anxiety-regulating nuclei, would have little effect on EPM behavior but would also increase locomotor activity.
Section snippets
Animals
Adult, male Long–Evans rats (N = 32; 201–225 g, Charles River Laboratories International, Inc., Kingston, NY, USA) were individually housed in an AAALAC-accredited facility, on a 12-hour reversed light/dark cycle (lights off at 0900 h). They were given at least one week to acclimate to the facility prior to surgery and were handled daily. Rats received ad libitum chow (PicoLab Rodent Diet 20 5053, Lab Diet, St. Louis, MO, USA) and water throughout the study. Experiments were approved by the
Results
In the novel activity chamber, drug injection in the PVT subregions significantly affected locomotor activity [F (3,25) = 18.94, p < 0.001] (Fig. 1). Multiple comparisons revealed that this was due to a significant reduction in activity after bac + mus compared to saline in both the aPVT (p < 0.01) and pPVT subregions (p < 0.001), with a trend for a difference between the aPVT and pPVT groups after bac + mus injection (p = 0.09) but, importantly, no significant difference between these groups after injection
Discussion
The results of this study suggest that, while both the aPVT and pPVT are necessary for general locomotor activity, the pPVT has a greater role in novelty-induced activity and is the only subregion necessary for the expression of anxiety-like behavior. These results confirm our original hypothesis that both subregions contribute to emotional behavior and that the pPVT plays a greater role in reactions to stressful stimuli, but the direction of effects induced by GABA agonists is contrary to that
Acknowledgements
This research was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Numbers K99AA021782/R00AA021782 (J.R.B.) and R01AA12882 (S.F.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We extend gratitude to Hui Tin Ho and Mohammad I. Alam for their technical assistance.
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