Regulation of Fear Responses by Striatal and Extrastriatal Adenosine A2A Receptors in Forebrain

Abstract

Background Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extra-striatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. Methods We tested two brain region-specific A2AR knockout lines with A2ARs selectively inactivated either in the striatum only (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex, fb-A2AR KO) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of AAV5-Cre into conditional (floxed)-A2AR knockout mice. Results Selective deletion of striatal A2ARs in st-A2AR KO mice increased Pavlovian fear conditioning (both context and tone), but when the A2AR deletion was extended to include extra-striatal regions in fb-A2AR KO mice, context fear conditioning was normalized and tone fear conditioning was attenuated. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests and increased the startle response. These extra-striatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. Conclusions This study provides the first evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning while inactivation of extra-striatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…This was not due to an effect of caffeine or of selective A 2A R antagonists on nociception, as we used a dose of SCH58261 one order of magnitude smaller than the minimum dose previously shown to have no effect on nociception (Bastia et al, 2002). Instead, the different impact of the global A 2A R blockade compared with the blockade of A 2A Rs selectively in the amygdala indicates that the impact of A 2A Rs on fear memory is unlikely to be restricted to the amygdala, in accordance with the previously reported ability of hippocampal A 2A Rs to interfere with contextual fear and the opposite effect of amygdala and striatal A 2A Rs on the control of the expression of fear memory (Wei et al, 2014), as summarized in Figure 5d. In fact, the acquisition and recall of conditioned fear also involves other limbic and neocortical areas in partially redundant circuits (Orsini and Maren, 2012).…”

“…In fact, the acquisition and recall of conditioned fear also involves other limbic and neocortical areas in partially redundant circuits (Orsini and Maren, 2012). Similarly, it is possible that the selective deletion of A 2A Rs in the amygdala might bolster the impact of otherwise less relevant A 2A Rs in other brain regions, as we have previously observed to occur for the recruitment of striatal DARPP-32 (Shen et al, 2013), behavioral sensitization , or emotional responses (Wei et al, 2014) using cell-type-selective genetic eliminations of A 2A Rs. In fact, several studies have dissected the involvement of different brain regions in the processing of contextual and cued fear memory (Orsini and Maren, 2012), albeit the expression of both forms of contextual fear mostly depend on amygdala circuits (Goosens and Maren, 2001).…”

“…Similarly, additional studies are required to test if ATPderived adenosine is also the source of adenosine-activating A 2A Rs and if ATP is released during induction of synaptic plasticity in amygdala synapses, which is currently unknown. This parallel ability of A 2A Rs to control amygdala synaptic plasticity and fear-related responses also raises the question of disentangling if A 2A Rs are continuously affecting an abnormal functioning of amygdala circuits, as suggested by the sustained upregulation of A 2A Rs in the amygdala after fear acquisition, or if instead A 2A Rs are critically required for a state-dependent shift on exposure to fear, as suggested by the ability of A 2A Rs to control the emotional status of rodents (Wei et al, 2014;Kaster et al, 2015).…”

“…The spontaneous locomotion of mice was measured 1 day after the fear conditioning protocols, in an open field test as described previously (Wei et al, 2014;Kaster et al, 2015). Nociceptive responses were evaluated 1 day after the open field test by using the hot-plate test (Le Bars et al, 2001).…”

Ginsenoside Rg1 Prevents Chronic Stress-Induced Depression-Like Behaviors and Neuronal Structural Plasticity in Rats

“…CREB, a key nuclear transcription factor, has been well documented in neuronal plasticity and long-term memory formation [17,18]. Its activation promotes the transcription and translation of BDNF, a crucial regulator involved in providing lifelong protection and regulation of neuronal structure and function [19][20][21]. It has been demonstrated that chronic stress leads to a reduction in hippocampal BDNF levels in rats [22], and clinical studies also indicated characteristic decreases in BDNF expression in the serum and amygdala of patients with major depressive disorders [23,24].…”