Abstract
The dorsolateral column of the periaqueductal gray (dlPAG) integrates aversive emotional experiences and represents an important site responding to life threatening situations, such as hypoxia, cardiac pain and predator threats. Previous studies have shown that the dorsal PAG also supports fear learning; and we have currently explored how the dlPAG influences associative learning. We have first shown that N-methyl-D-aspartate (NMDA) 100 pmol injection in the dlPAG works as a valuable unconditioned stimulus (US) for the acquisition of olfactory fear conditioning (OFC) using amyl acetate odor as conditioned stimulus (CS). Next, we revisited the ascending projections of the dlPAG to the thalamus and hypothalamus to reveal potential paths that could mediate associative learning during OFC. Accordingly, the most important ascending target of the dlPAG is the hypothalamic defensive circuit, and we were able to show that pharmacological inactivation using β-adrenoceptor blockade of the dorsal premammillary nucleus, the main exit way for the hypothalamic defensive circuit to thalamo-cortical circuits involved in fear learning, impaired the acquisition of the OFC promoted by NMDA stimulation of the dlPAG. Moreover, our tracing study revealed multiple parallel paths from the dlPAG to several thalamic targets linked to cortical-hippocampal-amygdalar circuits involved in fear learning. Overall, the results point to a major role of the dlPAG in the mediation of aversive associative learning via ascending projections to the medial hypothalamic defensive circuit, and perhaps, to other thalamic targets, as well. These results provide interesting perspectives to understand how life threatening events impact on fear learning, and should be useful to understand pathological fear memory encoding in anxiety disorders.
Highlights
In humans, activation of the periaqueductal gray (PAG) has been correlated with fear and anger manifestations in normal volunteers [1] and distress episodes in post traumatic stress disorder (PTSD) patients submitted to cue reminders of the trauma [2]
The defensive response exhibited during the 10 min conditioning session was represented by episodes of flight and jumping restricted to the first min after receiving NMDA into the dorsolateral PAG (dlPAG) (Table 1), followed by increased freezing time maintained throughout the first 5 min period of observation
We have shown that NMDA stimulation of the dlPAG works as a useful unconditioned stimulus (US) capable of supporting fear conditioning to a neutral olfactory cue
Summary
Activation of the periaqueductal gray (PAG) has been correlated with fear and anger manifestations in normal volunteers [1] and distress episodes in post traumatic stress disorder (PTSD) patients submitted to cue reminders of the trauma [2]. Recent structural neuroimaging data in human patients suggested the involvement of the PAG in panic disorders [3,4]. In line with this view, there is a growing body of evidence suggesting the PAG as a key locus to integrate panic-like responses. Stimulation of the dorsal PAG is known to induce paniclike responses [8,9,10] and is thought to work as a reliable animal model of panic attacks [11,12,13]. DlPAG stimulation evokes full blown defense, including freezing and flight behavior, as well as the accompanying sympathetic responses, such as exophtalmos, and increased heart rate and blood pressure [9,10]
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