Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats

Meloni, Edward G.; Venkataraman, Archana; Donahue, Rachel; Carlezon, William A.

doi:10.1016/j.psyneuen.2015.11.003

Cited by 33 publications

(42 citation statements)

References 61 publications

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“…PACAP is highly preserved across species, permitting the use of transgenic animal models to inform our understanding of PACAP as related to fear, stress, and anxiety. Animal models examining PACAP and PAC1 receptor function using transgenic models have implicated PACAP/PAC1R in anxiety responses, startle and fear behavior, memory, pain, and hypothalamic–pituitary–adrenal function/responsiveness (including normal and stress‐evoked corticosterone responses (Hammack & May, ; Meloni, Venkataraman, Donahue, & Carlezon, ). Consistent with evidence for the effects of PACAP/PAC1R on regulation of expression of CRH activity, a critical role of PACAP expression and signaling has been observed in the bed nucleus of the stria terminalis, the central nucleus of the amygdala, and the basolateral amygdala (Hammack & May, ; Lezak et al., ; Mustafa, ).…”

Section: Discussionmentioning

confidence: 99%

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta‐Analysis

Lind

Marraccini

Sheerin

et al. 2017

Journal of Traumatic Stress

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Recent studies point to the potential role of the (pituitary) adenylate cyclase activating polypeptide receptor 1 (ADCYAP1R1) gene, which has been implicated in stress response, in posttraumatic stress disorder (PTSD). Multiple genetic association studies have examined potential PTSD risk related to this gene, with mixed results. We conducted a meta-analysis of rs2267735 in ADCYAP1R1 in PTSD. A literature search was conducted using PubMed and PsycINFO, resulting in nine studies that met criteria for inclusion in analysis. Biostat’s Comprehensive Meta-Analysis was used to conduct the main meta-analysis on the combined sex sample, as well as two subanalyses examining effects separately in female and male participants. Results indicated that the C allele of rs2267735 conferred significant risk for PTSD in the combined sex data, OR = 1.210, 95% CI [1.007, 1.454], p = .042, and in the subsample of women and girls, OR = 1.328, 95% CI [1.026, 1.719], p = .031; but not in the subsample of men and boys, OR = 0.964, 95% CI [0.733, 1.269], p = .796. These results provide evidence for an association between ADCYAP1R1 and PTSD and indicate that there may indeed be sex differences. Implications of these findings, including the role of rs2267735 as one modulator of the stress system, are discussed.

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Section: Discussionmentioning

confidence: 99%

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta‐Analysis

Lind

Marraccini

Sheerin

et al. 2017

Journal of Traumatic Stress

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“…Mice lacking the PAC1R either globally or in the hippocampus and neocortex showed impaired contextual fear conditioning (Otto et al, 2001). PACAP delivered intracerebroventricularly in rats enhanced the consolidation of a passive avoidance memory at low doses (Sacchetti et al, 2001) and temporarily impaired contextual fear memory at high doses (Meloni et al, 2016). PACAP delivered directly into the hippocampus enhanced the consolidation of a contextual fear memory (Schmidt et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats

et al. 2018

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A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues.

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“…High blood levels of PACAP, especially in females, and methylation of PAC1 in a sex-independent manner were previously associated with PTSD [11]. In rodents, PACAP has been shown to enhance consolidation and extinction of contextual fear and enhance excitatory synaptic transmission in projections from BLA to lateral division of CN [43][44][45][46]. Given the role of PACAP and PAC1 in contextual fear, we chose to delineate the role of the PACAP and PAC1 in the BMA and mICCs microcircuitry in regulation of different aspects of contextual fear behaviors in both male and female mice.…”

Section: Discussionmentioning

confidence: 99%

A peptidergic amygdala microcircuit modulates sexually dimorphic contextual fear

Rajbhandari

Octeau

Gonzalez

et al. 2020

Preprint

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Trauma can cause dysfunctional fear regulation leading some to develop disorders like post-traumatic stress disorder (PTSD). The amygdala regulates fear, and, PACAP and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs). In vivo optogenetic stimulation of this pathway increased cfos expression in mICCs, decreased fear retention and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICCs PACAPergic pathway produced excitatory postsynaptic currents (EPSCs) in mICCs neurons, which was enhanced by PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sexdependent manner via the microcircuit containing the BMA and mICCs, dependent on behavioral state. Results 1.PACAP-expressing neurons in the BMA innervate the medial ICCs We examined EGFP expression in the Adcyap1-EGFP mice, which restricts EGFP expression to PACAP expressing neurons [12]. Although distributed broadly in the amygdala, EGFP + cells were enriched in the lateral and basomedial nucleus (BMA) subregion with fibers in the mICCs (Fig. 1A and Fig. S1A, B). We evaluated the local afferents of BMA and found a majority of PACAPergic neurons in the BMA innervate the dorsal and ventral mICCs (Fig.1A). By comparison, we found little to no innervation of the CN by EGFP + neurons (Fig 1A. and Fig. S1B). The pattern of expression corresponds with PACAP mRNA expression, which is high in the BMA and with some expression in the mICCS (Allen Brain Atlas Mouse Brain In Situ hybridization) (Fig. S1C). To further confirm the existence of monosynaptic PACAPergic projections from BMA to mICC we used an intersectional approach as described in Fenno et. al. 2014 [13]. For this, we injected a retrogradely trafficked Cre-dependent HSV virus (hEF1α-LS1L-mCherry-IRES-flpo) into the mICCs (dorsal portion) and a Flp-dependent AAV5-EF1a-fDIO-ChR2-eYFP-WPRE into the BMA of Adcyap1-2A-Cre. Adcyap1-2A-Cre mice express Cre specifically in PACAP-containing neurons. With the intersectional approach, the HSV virus, which is Credependent and expresses FLP, retrogradely transports allowing expression specifically in PACAPergic neurons in the BMA. The AAV viruses in turn are FLP-dependent, so therefore expresses only in neurons that have FLP. This allows labeling specific projections from the BMA to mICCs. Thus, using two different approaches, we were able to confirm that PACAPergic (Adcyap1-EGFP) neurons in the BMA innervate mICCs (Fig. 1B and Fic. 1C). 2.In vivo optogenetic stimulation of BMA PACAPergic input to the mICCs decreases fear retention and increases fear extinction

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Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats

Cited by 33 publications

References 61 publications

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta‐Analysis

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta‐Analysis

Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats

A peptidergic amygdala microcircuit modulates sexually dimorphic contextual fear

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