) now activate these neurons. Indeed, a single footshock (Amat et al., 1998b) and even the mere presence of a juvenile (Christianson et al., 2010) lead to activation

of DRN 5-HT neurons if the subjects had experienced IS a day earlier. Without prior IS no activation at all was observed in response to these mild stressors. A number of mechanisms are likely responsible for this uncontrollable-stress induced sensitization of DRN 5-HT neurons. One mechanism for which there is strong evidence concerns 5-HT1A inhibitory autoreceptors present on the soma and dendrites of DRN 5-HT cells. As noted above, IS leads to the accumulation of very high extracellular levels of 5-HT within the DRN itself, with this elevation persisting for a number of hours (Maswood et al., 1998). Rozeske et al. (2011) have shown that this 5-HT accumulation desensitizes these LY294002 inhibitory CDK inhibitor autoreceptors for a number of days, thereby reducing the normal inhibitory control over these neurons. Why does an uncontrollable stressor

produce a greater activation of DRN 5-HT neurons than does a physically identical controllable stressor? One possibility is that this is intrinsic to the DRN, with the DRN itself detecting presence versus absence of behavioral control. However, this is most unlikely. In order to detect whether a tailshock is or is not controllable, that is, whether there is a contingency between behavioral responses and shock termination, a structure must receive sensory input indicating whether the stressor is present or not, and detailed motor input indicating whether a behavioral responses has or has not occurred. The tuclazepam DRN does not receive detailed sensory or motor input from cortical areas (Peyron et al., 1998). If s structure does not receive information as to whether a stressor is present or not, nor whether a behavior has occurred, it cannot detect control. This suggests that the DRN cannot operate

in isolation and must receive inputs from other regions, thereby leading to its activation by IS. An obvious explanation for the dierential activation of DRN 5-HT neurons by IS relative to ES would be that ES does not lead to these inputs, or does so to a lessor degree. Here, the protective effects of ES would be produced passively, that is, by an absence of some “drive” to the DRN that is produced by IS. Therefore, we have examined a number of inputs to the DRN that stimulate DRN 5-HT activity during exposure to the IS stressor. We have found 3 that are clear: a CRH input, likely from the BNST; a noradrenergic (NE) input, likely from the locus coeruleus (LC), and a glutamate (GLU) input, likely from the habenula. Thus, blockade of CRH receptors (Hammack et al., 2002 and Hammack et al., 2003), NE receptors (Grahn et al., 2002) or GLU receptors (Grahn et al.