Interestingly, the DRN receives all, or virtually all, of its cortical inputs from infralimbic (IL) and prelimbic (PL) regions of the medial prefrontal cortex (mPFC).23 The mPFC is involved with mediating “executive functions”24; functions that are consistent with behavioral control detection. Furthermore, the mPFC has been shown to be a key site in “contingency learning” as opposed to habit formation,25

a process very close to control learning. IL and PL regions, which comprise the Inhibitors,research,lifescience,medical ventral mPFC (mPFCv) send excitatory glutamatergic projections to the DRN.26 However, within the DRN these pyramidal glutamatergic projections synapse preferentially onto yaminobutyric acid (GABA) – ergic interneurons that inhibit the 5-HT cells.26 As would be expected from this anatomy, Inhibitors,research,lifescience,medical electrical stimulation of regions of the mPFCv that contain output neurons to the DRN leads to inhibition of 5-HT activity within the DRN.27,28 The fact that activation of mPFCv output to the DRN actively

inhibits DRN 5-HT activity immediately suggests that if the mPFCv is indeed involved in control/lack of control detection, then perhaps it is really control that is the active ingredient, leading to mPFCv-mediated active inhibition of the DRN when it is present. Here the idea is that aversive stimulation per se drives the DRN, Inhibitors,research,lifescience,medical and when the presence of behavioral control is detected Inhibitors,research,lifescience,medical by the mPFCv, the DRN, and perhaps other stress-responsive limbic and brain stem structures (see below) are actively inhibited. In our first attempt to test the role of the mPFCv, we inactivated the mPFCv during exposure to IS and ES by microinjecting muscimol into the region.29 Muscimol is a GABA agonist, and so inhibits the activity of cells that express GABA receptors, such as the pyramidal output neurons. Inactivating the mPFCv did indeed eliminate the differential effects

of controllability – that is, IS and ES now produced the same Inhibitors,research,lifescience,medical outcomes. However, mPFCv inactivation FK228 nmr eliminated the IS-ES in a particular way The presence of control was no longer protective, and now ES as well as IS produced later escape learning failure and exaggerated fear conditioning. Furthermore, ES now activated the DRN to the same degree as did IS. Inactivating the mPFCv did not make IS better or worse; it acted only in ES subjects to eliminate the protective effect of control. It is important to why note that muscimol microinjection did not retard the learning of the wheelturn escape response during ES by the ES subjects. That is, the ES subjects turned the wheel and terminated the tailshocks, but did not benefit from the experience. This is in keeping with data indicating that the mPFC is not involved in the learning of habits or motor responses, but rather in more complex cognitive aspects of behavior.