Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide that regulates neuronal physiology and transcription through Gs/Gq-coupled receptors. Its actions within hypothalamic, limbic, and mnemonic systems underlie its roles in stress regulation, affective processing, neuroprotection, and cognition. Recently, elevated PACAP levels and genetic disruption of PAC1 receptor signaling in humans has been linked to maladaptive threat learning and pathological stress and fear in post-traumatic stress disorder (PTSD). PACAP is positioned to integrate stress and memory in PTSD for which memory of the traumatic experience is central to the disorder. However, PACAP’s role in memory has received comparatively less attention than its role in stress. In this review, we consider the evidence for PACAP-PAC1 receptor signaling in learning and plasticity, discuss emerging data on sex differences in PACAP signaling, and raise key questions for further study toward elucidating the contribution of PACAP to adaptive and maladaptive fear learning.
Introduction
The salient experiences of our daily life create memories that form the narrative of our self. These memories enrich our connections with others and guide our decisions and behavior, but if born out of pain and trauma, can be debilitating. Intrusive, terrifying memories that are difficult to extinguish or that generalize to non-threatening situations are the hallmark of post-traumatic stress disorder (PTSD), a complex disorder with a lifetime prevalence of about 8% (Kessler et al., 1995; Kilpatrick et al., 2013). PTSD is characterized by altered stress reactivity, generalized fear to non-threatening cues and situations, and is more prevalent in females (Kessler et al., 1995; Kilpatrick et al., 2013). Recently, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been linked to PTSD (Ressler et al., 2011; ; Uddin et al., 2013). This link has been attributed to the role that PACAP plays in regulating the somatic and affective components of chronic stress, discussed in excellent reviews (; King et al., 2017b; Miles and Maren, 2019). However, PACAP’s role in memory has received comparatively less attention yet may also contribute to PTSD for which memory of the traumatic experience is central to the disorder. Here, we briefly review the literature supporting a role for PACAP in memory formation and discuss avenues for further investigation.
PACAP, an Overview
Pituitary adenylate cyclase-activating polypeptide is a highly conserved pleiotropic neuropeptide in the vasoactive intestinal peptide (VIP)/secretin/glucagon family that modulates several physiological functions in the periphery and central nervous system via class B G-protein coupled receptors (Miyata et al., 1989, 1990; ; Piggins et al., 1996; ; Vaudry et al., 2009). In the brain, the 38-amino acid form of PACAP predominates (), and PACAP-38 and its receptors are widely expressed in circuits involved in memory, stress, and affect (Shioda et al., 1997; ; Joo et al., 2004; ). PACAP modulates neuronal function via the PACAP-specific high-affinity receptor PAC1 and the VPAC1 and VPAC2 receptors, which have similar affinity for PACAP and VIP. These receptors are coupled to Gαs, but PAC1 can also signal through Gαq (Spengler et al., 1993; ; Vaudry et al., 2009; ). Thus, PACAP can regulate the neuronal excitability and synaptic plasticity underlying memory and cognition through a diverse set of cAMP-mediated intracellular signaling (for a review see ).
Distributed Memory Systems
A role for PACAP in learning and memory was evident from early examinations of mice lacking the PAC1 receptor (PAC1R). Genetic deletion of PAC1R either globally or in the forebrain produced mild to severe impairments in certain forms of hippocampus-dependent learning (Sauvage et al., 2000; Otto et al., 2001a, b). Contextual fear conditioning, an associative paradigm in which subjects learn to associate the spatial configuration of environmental cues with a footshock, was impaired, while other hippocampus-dependent learning tasks, the Morris water maze and social transmission of food preference were unaffected. Hippocampus-independent cued fear conditioning was also unaffected by the loss of PAC1R signaling in the same study. Global knockouts displayed anxiety-like behavior and altered stress reactivity, which is consistent with PACAP’s role in HPA axis regulation, but which could affect the conditional response of freezing used to assess memory in rodent fear conditioning. Thus, it is important that the forebrain-specific knockouts, which showed the same memory deficit, did not differ from wild-type controls in locomotor activity or anxiety-like activity in the open field or elevated plus maze (Otto et al., 2001b). Mice lacking the PACAP peptide also showed impaired contextual fear memory as well as deficits in novel object recognition (Takuma et al., 2014). However, these mice exhibit a wide range of altered behavior (reviewed in ). Some of these behaviors could be ameliorated with environmental enrichment early in life, but not in adulthood, suggesting that PACAP’s role in neural development may contribute to abnormal behaviors in PACAP deficient mice (; Takuma et al., 2014). Nonetheless, exogenous delivery of PACAP intracerebroventricularly into adult 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, 2018). These studies demonstrate a role for forebrain PACAP in contextual fear learning and suggest that PAC1R signaling may be preferentially engaged by aversive events.
More recently, behavioral pharmacology studies have identified specific brain regions where PACAP contributes to aversive memory or its extinction. These include the hippocampus, amygdala, and prelimbic cortex. In the hippocampus, the consolidation of contextual fear memory was enhanced by PACAP and impaired by the PAC1R antagonist PACAP6-38, when injected immediately after training (Schmidt et al., 2015). Hippocampal PACAP also contributes to fear extinction, while amygdala PACAP is needed for contextual fear memory but not its extinction (Schmidt et al., 2015). The subregional specificity of PACAP’s effects in the hippocampus remain to be determined. The hippocampus is functionally heterogeneous with unique output connectivity along its dorsal-ventral axis (). These studies targeted dorsal hippocampus and given the importance of ventral hippocampus to affective behavior and learning, future work should examine ventral hippocampal PACAP. PACAP also participates in the formation of trace fear memory, a form of cued fear learning dependent on the prelimbic cortex and hippocampus in addition to the amygdala (Kirry et al., 2018). Trace conditioning requires the association of a cue and shock separated in time, and linking these events requires sustained neuronal activity in prelimbic cortex (; ; , ). Prelimbic injection of PACAP6-38 prior to training impaired the formation of the cued memory in females, but not males (Kirry et al., 2018). This sex difference, discussed below, may provide insight into the genetic link between PAC1R and PTSD, for which women with a genetic polymorphism in the PAC1R gene exhibit enhanced reactivity to threat-predictive cues (Ressler et al., 2011). The prefrontal cortex is also needed for aspects of contextual fear learning (; ; Rozeske et al., 2015; ; Twining et al., 2020), but PAC1R antagonism did not affect the contextual fear memory formed alongside the cued fear memory in trace conditioning (Kirry et al., 2018). Nor did the manipulation affect a non-aversive spatial-working memory T-maze task in either sex. These data suggest that PAC1R signaling contributes to prefrontal mechanisms of working memory or sustained attention required for predicting threat based on available cues. Together, these studies demonstrate a role for PACAP signaling in learning and memory and point to site-specific engagement of PACAP in cued and contextual fear.
Cellular and Synaptic Physiology
The regulation of synaptic glutamatergic signaling and the production of new proteins for long-term synaptic stabilization are the basis of the cellular consolidation of memory, a process that generally concludes within a few hours after training (McGaugh, 2000; ). Adenylate cyclase/cAMP-driven intracellular signaling leading to CREB-mediated gene transcription is critical for the formation of long-term memories (Kandel et al., 2014; ). PACAP’s namesake ability to activate these signaling cascades underlies its role in memory. In hippocampal circuits, PACAP modulates synaptic and evoked NMDA- and AMPA-mediated currents via PKA or PLC/PKC (Roberto and Brunelli, 2000; Roberto et al., 2001; ; Yaka et al., 2003; Macdonald et al., 2005; ; Pecoraro et al., 2017). PACAP-dependent phosphorylation of NMDA receptor subunits promotes mossy fiber long-term potentiation (LTP), a cellular correlate of learning and memory, and LTP is impaired in mice lacking PACAP or PAC1R (Otto et al., 2001a; Matsuyama et al., 2003). PACAP’s effects on plasticity are dose-dependent, with higher doses exerting inhibitory effects on hippocampal synaptic transmission via VPAC signaling (), which reflects its dose-dependent effects on hippocampus-dependent fear memory (Sacchetti et al., 2001; Meloni et al., 2016). It is important to note that temperature is an important factor in the physiological investigation of PACAP. While lower temperatures (e.g., 21–24°C) are useful for slowing down the fast ion channel kinetics linked to PAC1R activation (), they can alter other measures of excitability and interfere with PAC1R endosomal signaling (Merriam et al., 2013). Moreover, the majority of existing hippocampal work has focused on CA1 and CA3, but PAC1R is expressed also in the dentate gyrus (; Joo et al., 2004). Recent work has shown that PACAP-PAC1R activation drives CREB-mediated transcription and promotes excitability of DG granule cells (; ; ).
Pituitary adenylate cyclase-activating polypeptide has dose-, receptor-, and circuit-specific effects on physiology in other brain areas, which highlights the potential ways in which PACAP can affect learning within a distributed network. In the amygdala, PACAP increases AMPA-mediated currents at BLA-CeA synapses via VPAC1 () and increases GABA release via PAC1R (Varodayan et al., 2019), mechanisms that underlie affective behavioral responses to chronic stress or pain. In the central nucleus of the amygdala, fear conditioning drives expression of the plasticity-related protein Arc and intracerebroventricular infusion of PACAP enhances this expression (Meloni et al., 2018). Arc, whose translation is regulated by PKA activity (), is critical to several cellular processes supporting memory and cognition (e.g., Nikolaienko et al., 2018). PACAP’s contribution to synaptic plasticity in cortical systems is not clear. Given the selective role for prelimbic PAC1R signaling in trace cued, but not contextual, memory (Kirry et al., 2018), PACAP may act on working-memory or sustained attention mechanisms. One candidate mechanism is the regulation of GluN2B-containing NMDARs, which promote recurrent activity in cortical circuits (Wang et al., 2013) and which are needed for trace cued, but not contextual fear learning in the prefrontal cortex and hippocampus (; ). PACAP has been shown to phosphorylate the GluN2B subunit in the hippocampus and hypothalamus to regulate glutamatergic signaling (Yaka et al., 2003; Resch et al., 2014).
Pituitary adenylate cyclase-activating polypeptide can also influence memory via modulation of intrinsic physiology (see Open Questions) and via developmental maturation of memory circuits (reviewed in Shen et al., 2013). For example, developmental knockout of VPAC2 which is sensitive to both VIP and PACAP prevented the formation of fear extinction memory in adulthood (). Importantly, VPAC2-KO mice had reduced cell size and dendritic branching in the prelimbic cortex, morphological changes similar to those observed after chronic corticosterone exposure and chronic stress, conditions which also produce fear extinction deficits (Wellman, 2001; Radley et al., 2004, 2006; Moench and Wellman, 2017; reviewed in Wellman et al., 2020). Whether impaired extinction in VPAC2-KO mice is a consequence of altered prefrontal morphology or lack of PACAP/VIP signaling at VPAC2 in the prefrontal-amygdala circuit during extinction learning remains to be determined. Nonetheless, these neuropeptides are necessary for proper neural maturation, and pathological disruptions in PACAP signaling during critical developmental windows could thus affect adult cognition by altering the development of memory-related circuits. Although we are only beginning to elucidate the diverse mechanisms by which PACAP affects learning and memory, the significant work on the diversity of PACAP signaling in stress-related behaviors provides a useful foundation for rapid progress in this effort (; ; ).
Sex Differences
The work above implicates PACAP and PAC1R in neuroplasticity and memory and suggests that endogenous PACAP released during salient, aversive events contributes to memories for threat-predictive cues and contexts. Therefore, vulnerabilities in PACAP signaling may contribute to pathological fear in PTSD through its roles in learning and in mediating traumatic stress responses. Further investigation of the PACAP-PTSD link requires inclusion of female subjects, not only because females have largely been excluded from preclinical study, but also because of a sex-specific link between PACAP and PTSD. A single-nucleotide polymorphism (SNP) in the adcyap1r1 gene encoding PAC1R is associated with symptom severity in women, but not men; altered DNA methylation of the same gene is associated with PTSD in both sexes (Ressler et al., 2002; ). The risk allele for PTSD is also associated with symptom severity in GAD females, but not males (Ross et al., 2020). The SNP is located in an estrogen-response element (ERE), and the nucleotide change interferes with estradiol-estrogen receptor alpha binding the ERE, leading to a decrease in receptor expression (Mercer et al., 2016). This points to a potential mechanism of vulnerability in women. Indeed, several labs are actively examining how PACAP in the BNST and hypothalamic stress circuits regulates the affective response to stress in male and female rodents (King et al., 2017a, b; Ramikie and Ressler, 2018), and additional mechanistic insight may come from examination of sex differences in autonomic regulation by PACAP (Nakamachi et al., 2016). This work complements that of Bangasser, Valentino, and others detailing sex differences in the corticotropin-releasing factor (CRF) system and brainstem arousal systems [for excellent reviews, see ; Valentino and Bangasser (2016); ].
Little is known about sex differences in PACAP’s contribution to memory. Recent work showed that prelimbic PACAP participates in trace cued fear learning in females, but not males, and that mRNA levels for PAC1R are higher in females than males and further modulated by the estrous cycle (Kirry et al., 2018). Recently, Rajbhandari et al. (2021) reported increased fear generalization and impaired extinction in males, but not females, following viral deletion of PAC1R in the medial intercalated cells of the amygdala, a region involved in the suppression of fear following extinction (). Females in that study showed a reduced asymptotic level of fear during acquisition. These behavioral results suggest that PACAP signaling exerts sex and region-specific modulation of fear memories. In humans, the PTSD-related PAC1R risk allele is associated with enhanced startle to threat-related cues, impaired fear and safety discrimination, and altered hippocampal and amygdala reactivity in fear conditioning (Ressler et al., 2011; Jovanovic et al., 2013; Stevens et al., 2014). In children, females with the risk allele showed enhanced fear responding to threat-related cues 1 year after conditioning (Jovanovic et al., 2020). While these clinical studies implicate associative learning processes in the PAC1R-PTSD link, it is difficult to distinguish the unique contributions of associative learning vs stress reactivity. Preclinical investigations are critical in this endeavor.
Open Questions
Pituitary adenylate cyclase-activating polypeptide contributes to learning and memory under salient, usually aversive conditions. The diversity of its neural function places this pleiotropic signaling peptide in the company of several peptide factors, such as CRF and estradiol, that have a wide range of function beyond that for which they were initially characterized (; Taxier et al., 2020). This diversity likely underlies the influence that PACAP dysregulation appears to have in psychiatric illness, but also makes it challenging to determine the nature of that relationship. Here, we raise a few open questions to guide further investigation.
Open Question 1: Is PACAP’s Role in Learning Selective for Aversive Episodic Memory?
Disruption of PAC1R signaling affects the formation of associative fear memories dependent on episodic memory systems, such as contextual fear or trace fear conditioning, but leaves standard delay cued conditioning and spatial learning largely intact. Interestingly, the amnesiac gene in drosophila, which codes for a putative PACAP homolog, AMN, is necessary for odor-shock associative memory (Quinn et al., 1979; ; Turrel et al., 2018). While the receptor target(s) by which AMN mediates memory is unclear, the parallels in these behavioral observations raise the possibility that PACAP is selective for aversive learning; however, its role in appetitive or other non-aversive learning is largely untested. Thus, to determine PACAP selectivity to certain forms of memory, its contribution to non-aversive memory needs to be clarified. Importantly, PACAP and PAC1R manipulations in the mature circuit are needed to rule out learning deficits due to aberrant neural development of healthy memory circuits for which PACAP is implicated. To this point, the role for AMN in the development of associative memory systems was recently dissociated from its role in adult learning (Turrel et al., 2018).
Open Question 2: What Aspect of an Aversive Experience Recruits PACAP Signaling?
Pituitary adenylate cyclase-activating polypeptide is mobilized by repeated or chronic stressors or by persistent neuropathic pain states (; Mustafa, 2013), but release conditions in learning networks during relatively brief aversive events in fear conditioning are unknown. PACAP-expressing cells are found throughout learning circuits (; ), many of which robustly respond to shock delivery. One possibility is that the aversive shock reinforcer may trigger the co-release of PACAP at glutamatergic terminals, facilitating cAMP-mediated signaling in support of robust fear memory. Alternatively, any sufficiently salient or arousing experience may mobilize PACAP and promote the consolidation of memory. The development of tools that allow accurate measurement of peptide release in vivo provide the circuit-level resolution needed to determine when and where PACAP is released during learning (Muller et al., 2014; ).
Open Question 3: What Are the Unique Peptide-Receptor Signaling Contributions to Learning and Memory?
The unique contributions of PACAP and VIP at PAC1 and VPAC1/2 receptors in learning and memory are poorly understood. For instance, VPAC2 receptors have partially overlapping distribution patterns in several regions important for learning and memory (Lee et al., 2010), and developmental manipulation of VPAC2 affects extinction learning in adulthood (). Pharmacological dissociation of PACAP actions at PAC1R and VPAC2 is difficult as both are a target of the PAC1R antagonist PACAP6-38. Plus, as mentioned earlier, mechanistic dissection of these peptides in vitro is sensitive to experimental parameters such as temperature. Thus, new small molecule antagonists as well as gene-editing tools will be invaluable in revealing the rich complexity of mnemonic regulation by these peptides.
Open Question 4: Does PACAP Bias Allocation of Specific Circuits Into Memory?
One intriguing, but speculative, role for PACAP in memory is to bias the allocation of cells or circuits into memory as a consequence of psychological stress or aversive experience (Kondo et al., 1997). Neuronal excitability at the time of learning determines which neurons are allocated to the memory trace (Yiu et al., 2014; ; Sehgal et al., 2018; Josselyn and Tonegawa, 2020). In the amygdala, cells with reduced afterhyperpolarization (AHP) and increased CREB phosphorylation immediately prior to training are recruited into a fear memory (Yiu et al., 2014). PACAP reduces the slow AHP calcium-activated potassium current sIAHPvia cAMP/PKA to increase excitability and action potential firing in hippocampal CA1 and neocortical neurons (; Taylor et al., 2014). PACAP-elicited firing and PKA-dependent phosphorylation of CREB drive CREB-mediated transcription (). PACAP affects excitability and firing in a circuit-specific manner (e.g., ) and intrinsic properties can be modified by experience (Sehgal et al., 2013; ). Thus, PACAP released during stressful events or elevated PACAP following chronic stress or pain could influence which circuits are recruited into a memory trace. Addressing this possibility will shed light on how altered PACAP-PAC1R signaling in susceptible individuals corresponds with altered threat-associated memory in PTSD.
Concluding Remarks
Pituitary adenylate cyclase-activating polypeptide is a pleiotropic neuropeptide whose diverse signaling underlies its diversity of function including neural development, neuroprotection, stress regulation, autonomic activation, affective behavior, and memory. This in turn highlights the therapeutic potential of this peptide and receptor modulations, a potential that is discussed in this Research Topic and reflected in recent efforts to develop non-peptide small molecule compounds to selectively target PACAP receptors (; Takasaki et al., 2018). The link between PACAP-PAC1R and pathological fear learning and stress dysregulation in PTSD suggests another potential therapeutic use for such treatments. Realization of this potential requires continued efforts to address the role of PACAP in learning and in the complex interactions of stress and sex on memory.
Statements
Author contributions
MG and NF wrote and edited the manuscript. Both authors contributed to the article and approved the submitted version.
Funding
This work was supported by the National Institutes of Health (R15MH118601 to MG; F32MH122092 to NF) and the Charles E. Kubly Mental Health Center at Marquette University. Support for Open Access fees was provided by Marquette University.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
AgoY.Hayata-TakanoA.KawanaiT.YamauchiR.TakeuchiS.CushmanJ. D.et al (2017). Impaired extinction of cued fear memory and abnormal dendritic morphology in the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice.Neurobiol. Learn. Mem.145222–231. 10.1016/j.nlm.2017.10.010
2
Al-HasaniR.WongJ. T.MabroukO. S.McCallJ. G.SchmitzG. P.Porter-StranskyK. A.et al (2018). In vivo detection of optically-evoked opioid peptide release.eLife7:e36520.
3
AlmliL. M.MercerK. B.KerleyK.FengH.BradleyB.ConneelyK. N.et al (2013). ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females.Am. J. Med. Genet. B Neuropsychiatr. Genet.162B262–272. 10.1002/ajmg.b.32145
4
ArimuraA. (1998). Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems.Jpn. J. Physiol.48301–331. 10.2170/jjphysiol.48.301
5
ArimuraA.Somogyvari-VighA.MiyataA.MizunoK.CoyD. H.KitadaC. (1991). Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes.Endocrinology1292787–2789. 10.1210/endo-129-5-2787
6
AsokA.LeroyF.RaymanJ. B.KandelE. R. (2019). Molecular mechanisms of the memory trace.Trends Neurosci.4214–22. 10.1016/j.tins.2018.10.005
7
BaegE. H.KimY. B.JangJ.KimH. T.Mook-JungI.JungM. W. (2001). Fast spiking and regular spiking neural correlates of fear conditioning in the medial prefrontal cortex of the rat.Cereb. Cortex11441–451. 10.1093/cercor/11.5.441
8
BangasserD. A.ValentinoR. J. (2014). Sex differences in stress-related psychiatric disorders: neurobiological perspectives.Front. Neuroendocrinol.35303–319. 10.1016/j.yfrne.2014.03.008
9
BangasserD. A.EckS. R.Ordones SanchezE. (2019). Sex differences in stress reactivity in arousal and attention systems.Neuropsychopharmacology44129–139. 10.1038/s41386-018-0137-2
10
BaxterP. S.MartelM. A.McMahonA.KindP. C.HardinghamG. E. (2011). Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1.J. Neurochem.118365–378. 10.1111/j.1471-4159.2011.07330.x
11
BeebeX.DarczakD.Davis-TaberR. A.UchicM. E.ScottV. E.JarvisM. F.et al (2008). Discovery and SAR of hydrazide antagonists of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type 1 (PAC1-R).Bioorg. Med. Chem. Lett.182162–2166. 10.1016/j.bmcl.2008.01.052
12
BloomerW. A.VanDongenH. M.VanDongenA. M. (2008). Arc/Arg3.1 translation is controlled by convergent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways.J. Biol. Chem.283582–592. 10.1074/jbc.m702451200
13
CaiD. J.AharoniD.ShumanT.ShobeJ.BianeJ.SongW.et al (2016). A shared neural ensemble links distinct contextual memories encoded close in time.Nature534115–118. 10.1038/nature17955
14
ChoJ. H.ZushidaK.ShumyatskyG. P.CarlezonW. A.MeloniE. G.BolshakovV. Y. (2012). Pituitary adenylate cyclase-activating polypeptide induces postsynaptically expressed potentiation in the intra-amygdala circuit.J. Neurosci.3214165–14177. 10.1523/jneurosci.1402-12.2012
15
CirannaL.CavallaroS. (2003). Opposing effects by pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide on hippocampal synaptic transmission.Exp. Neurol.184778–784. 10.1016/s0014-4886(03)00300-5
16
CondroM. C.MatyniaA.FosterN. N.AgoY.RajbhandariA. K.VanC.et al (2016). High-resolution characterization of a PACAP-EGFP transgenic mouse model for mapping PACAP-expressing neurons.J. Comp. Neurol.5243827–3848. 10.1002/cne.24035
17
CostaL.SantangeloF.Li VolsiG.CirannaL. (2009). Modulation of AMPA receptor-mediated ion current by pituitary adenylate cyclase-activating polypeptide (PACAP) in CA1 pyramidal neurons from rat hippocampus.Hippocampus1999–109. 10.1002/hipo.20488
18
DickinsonT.Fleetwood-WalkerS. M. (1999). VIP and PACAP: very important in pain?Trends Pharmacol. Sci.20324–329. 10.1016/s0165-6147(99)01340-1
19
DicksonL.FinlaysonK. (2009). VPAC and PAC receptors: from ligands to function.Pharmacol. Ther.121294–316. 10.1016/j.pharmthera.2008.11.006
20
DongH. W.SwansonL. W.ChenL.FanselowM. S.TogaA. W. (2009). Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1.Proc. Natl. Acad. Sci. U. S. A.10611794–11799. 10.1073/pnas.0812608106
21
DunnA. R.KaczorowskiC. C. (2019). Regulation of intrinsic excitability: roles for learning and memory, aging and Alzheimer’s disease, and genetic diversity.Neurobiol. Learn. Mem.164:107069. 10.1016/j.nlm.2019.107069
22
DuvarciS.PareD. (2014). Amygdala microcircuits controlling learned fear.Neuron82966–980. 10.1016/j.neuron.2014.04.042
23
FeanyM. B.QuinnW. G. (1995). A neuropeptide gene defined by the Drosophila memory mutant amnesiac.Science268869–873. 10.1126/science.7754370
24
FerraraN. C.GilmartinM. R. (2020). “Pituitary adenylate cyclase-activating polypeptide (PACAP) in stress, pain, and learning,” in Handbook of Amygdala Structure and Function, ed.UrbanJ. H. (Amsterdam: Elsevier).
25
GaoC.GillM. B.TronsonN. C.GuedeaA. L.GuzmanY. F.HuhK. H.et al (2010). Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation.Hippocampus201072–1082. 10.1002/hipo.20705
26
GilmartinM. R.HelmstetterF. J. (2010). Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex.Learn. Mem.17289–296. 10.1101/lm.1597410
27
GilmartinM. R.McEchronM. D. (2005). Single neurons in the medial prefrontal cortex of the rat exhibit tonic and phasic coding during trace fear conditioning.Behav. Neurosci.1191496–1510. 10.1037/0735-7044.119.6.1496
28
GilmartinM. R.BalderstonN. L.HelmstetterF. J. (2014). Prefrontal cortical regulation of fear learning.Trends Neurosci.37455–464. 10.1016/j.tins.2014.05.004
29
GilmartinM. R.KwapisJ. L.HelmstetterF. J. (2013a). NR2A-and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning.Learn. Mem.20290–294. 10.1101/lm.030510.113
30
GilmartinM. R.MiyawakiH.HelmstetterF. J.DibaK. (2013b). Prefrontal activity links nonoverlapping events in memory.J. Neurosci.3310910–10914. 10.1523/jneurosci.0144-13.2013
31
HammackS. E.MayV. (2015). Pituitary adenylate cyclase activating polypeptide in stress-related disorders: data convergence from animal and human studies.Biol. Psychiatry78167–177. 10.1016/j.biopsych.2014.12.003
32
HannibalJ. (2002). Pituitary adenylate cyclase-activating peptide in the rat central nervous system: an immunohistochemical and in situ hybridization study.J. Comp. Neurol.453389–417. 10.1002/cne.10418
33
HarmarA. J.FahrenkrugJ.GozesI.LaburtheM.MayV.PisegnaJ. R.et al (2012). Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1.Br. J. Pharmacol.1664–17. 10.1111/j.1476-5381.2012.01871.x
34
HashimotoH.ShintaniN.BabaA. (2006). New insights into the central PACAPergic system from the phenotypes in PACAP- and PACAP receptor-knockout mice.Ann. N. Y. Acad. Sci.107075–89. 10.1196/annals.1317.038
35
HerouxN. A.Robinson-DrummerP. A.SandersH. R.RosenJ. B.StantonM. E. (2017). Differential involvement of the medial prefrontal cortex across variants of contextual fear conditioning.Learn. Mem.24322–330. 10.1101/lm.045286.117
36
HuE.DemmouL.CauliB.GallopinT.GeoffroyH.Harris-WarrickR. M.et al (2011). VIP, CRF, and PACAP act at distinct receptors to elicit different cAMP/PKA dynamics in the neocortex.Cereb. Cortex21708–718. 10.1093/cercor/bhq143
37
HupaloS.BryceC. A.BangasserD. A.BerridgeC. W.ValentinoR. J.FlorescoS. B. (2019). Corticotropin-releasing factor (CRF) circuit modulation of cognition and motivation.Neurosci. Biobehav. Rev.10350–59. 10.1016/j.neubiorev.2019.06.010
38
HurleyM. M.RobbleM. R.CallanG.ChoiS.WheelerR. A. (2019). Pituitary adenylate cyclase-activating polypeptide (PACAP) acts in the nucleus accumbens to reduce hedonic drive.Int. J. Obes.43928–932. 10.1038/s41366-018-0154-6
39
IshihamaT.AgoY.ShintaniN.HashimotoH.BabaA.TakumaK.et al (2010). Environmental factors during early developmental period influence psychobehavioral abnormalities in adult PACAP-deficient mice.Behav. Brain Res.209274–280. 10.1016/j.bbr.2010.02.009
40
JaworskiD. M.ProctorM. D. (2000). Developmental regulation of pituitary adenylate cyclase-activating polypeptide and PAC(1) receptor mRNA expression in the rat central nervous system.Brain Res. Dev. Brain Res.12027–39. 10.1016/s0165-3806(99)00192-3
41
JohnsonG. C.MayV.ParsonsR. L.HammackS. E. (2019). Parallel signaling pathways of pituitary adenylate cyclase activating polypeptide (PACAP) regulate several intrinsic ion channels.Ann. N. Y. Acad. Sci.1455105–112. 10.1111/nyas.14116
42
JohnsonR. L.ParsonsG. C.MayV.HammackS. E. (2020). Pituitary adenylate cyclase-activating polypeptide-induced PAC1 receptor internalization and recruitment of MEK/ERK signaling enhance excitability of dentate gyrus granule cells.Am. J. Physiol. Cell Physiol.318C870–C878.
43
JohnsonR.ParsonsG. C.MayV.HammackS. E. (2020). The role of pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the hippocampal dentate Gyrus.Front. Cell. Neurosci.14:111.
44
JooK. M.ChungY. H.KimM. K.NamR. H.LeeB. L.LeeK. H.et al (2004). Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain.J. Comp. Neurol.476388–413. 10.1002/cne.20231
45
JosselynS. A.TonegawaS. (2020). Memory engrams: recalling the past and imagining the future.Science367:eaaw4325. 10.1126/science.aaw4325
46
JovanovicT.NorrholmS. D.DavisJ.MercerK. B.AlmliL.NelsonA.et al (2013). PAC1 receptor (ADCYAP1R1) genotype is associated with dark-enhanced startle in children.Mol. Psychiatry18742–743. 10.1038/mp.2012.98
47
JovanovicT.StensonA. F.ThompsonN.CliffordA.ComptonA.MintonS.et al (2020). Impact of ADCYAP1R1 genotype on longitudinal fear conditioning in children: interaction with trauma and sex.Neuropsychopharmacology451603–1608. 10.1038/s41386-020-0748-2
48
KandelE. R.DudaiY.MayfordM. R. (2014). The molecular and systems biology of memory.Cell157163–186. 10.1016/j.cell.2014.03.001
49
KesslerR. C.SonnegaA.BrometE.HughesM.NelsonC. B. (1995). Posttraumatic stress disorder in the national comorbidity survey.Arch. Gen. Psychiatry521048–1060. 10.1001/archpsyc.1995.03950240066012
50
KilpatrickD. G.ResnickH. S.MilanakM. E.MillerM. W.KeyesK. M.FriedmanM. J. (2013). National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria.J. Trauma Stress26537–547. 10.1002/jts.21848
51
KingS. B.LezakK. R.O’ReillyM.ToufexisD. J.FallsW. A.BraasK.et al (2017a). The effects of prior stress on anxiety-like responding to intra-BNST pituitary adenylate cyclase activating polypeptide in male and female rats.Neuropsychopharmacology421679–1687. 10.1038/npp.2017.16
52
KingS. B.ToufexisD. J.HammackS. E. (2017b). Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones.Stress20465–475. 10.1080/10253890.2017.1336535
53
KirryA. J.HerbstM. R.PoirierS. E.MaskeriM. M.RothwellA. C.TwiningR. C.et al (2018). Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats.Neuropharmacology133145–154. 10.1016/j.neuropharm.2018.01.010
54
KondoT.TominagaT.IchikawaM.IijimaT. (1997). Differential alteration of hippocampal synaptic strength induced by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38).Neurosci. Lett.221189–192. 10.1016/s0304-3940(96)13323-1
55
LeeJ. C.ChoY. J.KimJ.KimN.KangB. G.ChaC. I.et al (2010). Region-specific changes in the immunoreactivity of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC2, and PAC1 receptor) in the aged rat brains.Brain Res.135132–40. 10.1016/j.brainres.2010.06.048
56
MacdonaldD. S.WeerapuraM.BeazelyM. A.MartinL.CzerwinskiW.RoderJ. C.et al (2005). Modulation of NMDA receptors by pituitary adenylate cyclase activating peptide in CA1 neurons requires G alpha q, protein kinase C, and activation of Src.J. Neurosci.2511374–11384. 10.1523/jneurosci.3871-05.2005
57
MatsuyamaS.MatsumotoA.HashimotoH.ShintaniN.BabaA. (2003). Impaired long-term potentiation in vivo in the dentate gyrus of pituitary adenylate cyclase-activating polypeptide (PACAP) or PACAP type 1 receptor-mutant mice.Neuroreport142095–2098. 10.1097/00001756-200311140-00017
58
McGaughJ. L. (2000). Memory–a century of consolidation.Science287248–251. 10.1126/science.287.5451.248
59
MeloniE. G.KayeK. T.VenkataramanA.CarlezonW. A. (2018). PACAP increases Arc/Arg 3.1 expression within the extended amygdala after fear conditioning in rats.Neurobiol. Learn. Mem.15724–34. 10.1016/j.nlm.2018.11.011
60
MeloniE. G.VenkataramanA.DonahueR. J.CarlezonW. A. (2016). Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats.Psychoneuroendocrinology6412–21. 10.1016/j.psyneuen.2015.11.003
61
MercerK. B.DiasB.ShaferD.MaddoxS. A.MulleJ. G.HuP.et al (2016). Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.Transl. Psychiatry6:e978. 10.1038/tp.2016.241
62
MerriamL. A.BaranC. N.GirardB. M.HardwickJ. C.MayV.ParsonsR. L. (2013). Pituitary adenylate cyclase 1 receptor internalization and endosomal signaling mediate the pituitary adenylate cyclase activating polypeptide-induced increase in guinea pig cardiac neuron excitability.J. Neurosci.334614–4622. 10.1523/jneurosci.4999-12.2013
63
MilesO. W.MarenS. (2019). Role of the bed nucleus of the Stria terminalis in PTSD: insights from preclinical models.Front. Behav. Neurosci.13:68.
64
MiyataA.ArimuraA.DahlR. R.MinaminoN.UeharaA.JiangL.et al (1989). Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.Biochem. Biophys. Res. Commun.164567–574. 10.1016/0006-291x(89)91757-9
65
MiyataA.JiangL.DahlR. D.KitadaC.KuboK.FujinoM.et al (1990). Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38).Biochem. Biophys. Res. Commun.170643–648. 10.1016/0006-291x(90)92140-u
66
MoenchK. M.WellmanC. L. (2017). Differential dendritic remodeling in prelimbic cortex of male and female rats during recovery from chronic stress.Neuroscience357145–159. 10.1016/j.neuroscience.2017.05.049
67
MullerA.JosephV.SlesingerP. A.KleinfeldD. (2014). Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex.Nat. Methods111245–1252. 10.1038/nmeth.3151
68
MustafaT. (2013). Pituitary adenylate cyclase-activating polypeptide (PACAP): a master regulator in central and peripheral stress responses.Adv. Pharmacol.68445–457.
69
NakamachiT.OhtakiH.SekiT.YofuS.KagamiN.HashimotoH.et al (2016). PACAP suppresses dry eye signs by stimulating tear secretion.Nat. Commun.7:12034.
70
NikolaienkoO.PatilS.EriksenM. S.BramhamC. R. (2018). Arc protein: a flexible hub for synaptic plasticity and cognition.Semin. Cell Dev. Biol.7733–42. 10.1016/j.semcdb.2017.09.006
71
OttoC.KovalchukY.WolferD. P.GassP.MartinM.ZuschratterW.et al (2001a). Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice.J. Neurosci.215520–5527. 10.1523/jneurosci.21-15-05520.2001
72
OttoC.MartinM.WolferD. P.LippH. P.MaldonadoR.SchutzG. (2001b). Altered emotional behavior in PACAP-type-I-receptor-deficient mice.Brain Res. Mol. Brain Res.9278–84. 10.1016/s0169-328x(01)00153-x
73
PecoraroV.SardoneL. M.ChisariM.LicataF.Li VolsiG.PerciavalleV.et al (2017). A subnanomolar concentration of pituitary adenylate cyclase-activating polypeptide (PACAP) pre-synaptically modulates glutamatergic transmission in the rat hippocampus acting through acetylcholine.Neuroscience340551–562. 10.1016/j.neuroscience.2016.10.061
74
PigginsH. D.StampJ. A.BurnsJ.RusakB.SembaK. (1996). Distribution of pituitary adenylate cyclase activating polypeptide (PACAP) immunoreactivity in the hypothalamus and extended amygdala of the rat.J. Comp. Neurol.376278–294. 10.1002/(sici)1096-9861(19961209)376:2<278::aid-cne9>3.0.co;2-0
75
QuinnW. G.SziberP. P.BookerR. (1979). The Drosophila memory mutant amnesiac.Nature277212–214. 10.1038/277212a0
76
RadleyJ. J.RocherA. B.MillerM.JanssenW. G.ListonC.HofP. R.et al (2006). Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.Cereb. Cortex16313–320. 10.1093/cercor/bhi104
77
RadleyJ. J.SistiH. M.HaoJ.RocherA. B.McCallT.HofP. R.et al (2004). Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex.Neuroscience1251–6. 10.1016/j.neuroscience.2004.01.006
78
RajbhandariA. K.OcteauC. J.GonzalezS.PenningtonZ. T.MohamedF.TrottJ.et al (2021). A basomedial amygdala to intercalated cells microcircuit expressing PACAP and its receptor PAC1 regulates contextual fear.J. Neurosci.413446–3461. 10.1523/jneurosci.2564-20.2021
79
RamikieT.ResslerK. (2018). Mechanisms of sex differences in fear and posttraumatic stress disorder.Biol. Psychiatry83876–885. 10.1016/j.biopsych.2017.11.016
80
ReschJ. M.MaunzeB.PhillipsK. A.ChoiS. (2014). Inhibition of food intake by PACAP in the hypothalamic ventromedial nuclei is mediated by NMDA receptors.Physiol. Behav.133230–235. 10.1016/j.physbeh.2014.05.029
81
ResslerK. J.MercerK. B.BradleyB.JovanovicT.MahanA.KerleyK.et al (2011). Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.Nature470492–497.
82
ResslerK. J.PaschallG.ZhouX. L.DavisM. (2002). Regulation of synaptic plasticity genes during consolidation of fear conditioning.J. Neurosci.227892–7902. 10.1523/jneurosci.22-18-07892.2002
83
RobertoM.BrunelliM. (2000). PACAP-38 enhances excitatory synaptic transmission in the rat hippocampal CA1 region.Learn. Mem.7303–311. 10.1101/lm.34200
84
RobertoM.ScuriR.BrunelliM. (2001). Differential effects of PACAP-38 on synaptic responses in rat hippocampal CA1 region.Learn. Mem.8265–271. 10.1101/lm.40501
85
RossR. A.HoeppnerS. S.HellbergS. N.O’DayE. B.RosencransP. L.ResslerK. J.et al (2020). Circulating PACAP peptide and PAC1R genotype as possible transdiagnostic biomarkers for anxiety disorders in women: a preliminary study.Neuropsychopharmacology451125–1133. 10.1038/s41386-020-0604-4
86
RozeskeR. R.ValerioS.ChaudunF.HerryC. (2015). Prefrontal neuronal circuits of contextual fear conditioning.Genes Brain Behav.1422–36. 10.1111/gbb.12181
87
SacchettiB.LorenziniC. A.BaldiE.BucherelliC.RobertoM.TassoniG.et al (2001). Pituitary adenylate cyclase-activating polypeptide hormone (PACAP) at very low dosages improves memory in the rat.Neurobiol. Learn. Mem.761–6. 10.1006/nlme.2001.4014
88
SauvageM.BrabetP.HolsboerF.BockaertJ.StecklerT. (2000). Mild deficits in mice lacking pituitary adenylate cyclase-activating polypeptide receptor type 1 (PAC1) performing on memory tasks.Brain Res. Mol. Brain Res.8479–89. 10.1016/s0169-328x(00)00219-9
89
SchmidtS. D.MyskiwJ. C.FuriniC. R.SchmidtB. E.CavalcanteL. E.IzquierdoI. (2015). PACAP modulates the consolidation and extinction of the contextual fear conditioning through NMDA receptors.Neurobiol. Learn. Mem.118C120–124. 10.1016/j.nlm.2014.11.014
90
SehgalM.SongC.EhlersV. L.MoyerJ. R. (2013). Learning to learn - intrinsic plasticity as a metaplasticity mechanism for memory formation.Neurobiol. Learn. Mem.105186–199. 10.1016/j.nlm.2013.07.008
91
SehgalM.ZhouM.LaviA.HuangS.ZhouY.SilvaA. J. (2018). Memory allocation mechanisms underlie memory linking across time.Neurobiol. Learn. Mem.15321–25. 10.1016/j.nlm.2018.02.021
92
ShenS.GehlertD. R.CollierD. A. (2013). PACAP and PAC1 receptor in brain development and behavior.Neuropeptides47421–430. 10.1016/j.npep.2013.10.005
93
ShiodaS.ShutoY.Somogyvari-VighA.LegradiG.OndaH.CoyD. H.et al (1997). Localization and gene expression of the receptor for pituitary adenylate cyclase-activating polypeptide in the rat brain.Neurosci. Res.28345–354.
94
SpenglerD.WaeberC.PantaloniC.HolsboerF.BockaertJ.SeeburgP. H.et al (1993). Differential signal transduction by five splice variants of the PACAP receptor.Nature365170–175. 10.1038/365170a0
95
StevensJ. S.AlmliL. M.FaniN.GutmanD. A.BradleyB.NorrholmS. D.et al (2014). PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus.Proc. Natl. Acad. Sci. U. S. A.1113158–3163. 10.1073/pnas.1318954111
96
TakasakiI.WatanabeA.YokaiM.WatanabeY.HayakawaD.NagashimaR.et al (2018). In silico screening identified novel small-molecule antagonists of PAC1 receptor.J. Pharmacol. Exp. Ther.3651–18. 10.1124/jpet.117.245415
97
TakumaK.MaedaY.AgoY.IshihamaT.TakemotoK.NakagawaA.et al (2014). An enriched environment ameliorates memory impairments in PACAP-deficient mice.Behav. Brain Res.272269–278. 10.1016/j.bbr.2014.07.005
98
TaxierL. R.GrossK. S.FrickK. M. (2020). Oestradiol as a neuromodulator of learning and memory.Nat. Rev. Neurosci.21535–550. 10.1038/s41583-020-0362-7
99
TaylorR. D.MadsenM. G.KrauseM.Sampedro-CastanedaM.StockerM.PedarzaniP. (2014). Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways.Hippocampus2432–43. 10.1002/hipo.22201
100
TurrelO.GoguelV.PreatT. (2018). Amnesiac is required in the adult mushroom body for memory formation.J. Neurosci.389202–9214. 10.1523/jneurosci.0876-18.2018
101
TwiningR. C.LepakK.KirryA. J.GilmartinM. R. (2020). Ventral hippocampal input to the prelimbic cortex dissociates the context from the cue association in trace fear memory.J. Neurosci.403217–3230. 10.1523/jneurosci.1453-19.2020
102
UddinM.ChangS. C.ZhangC.ResslerK.MercerK. B.GaleaS.et al (2013). Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment.Depress. Anxiety30251–258. 10.1002/da.22037
103
ValentinoR. J.BangasserD. A. (2016). Sex-biased cellular signaling: molecular basis for sex differences in neuropsychiatric diseases.Dialogues Clin. Neurosci.18385–393. 10.31887/dcns.2016.18.4/rvalentino
104
VarodayanF. P.MinnigM. A.SteinmanM. S.OleataC. S.RileyM. W.SabinoV.et al (2019). PACAP regulation of central amygdala GABAergic synapses is altered by restraint stress.Neuropharmacology168:107752. 10.1016/j.neuropharm.2019.107752
105
VaudryD.Falluel-MorelA.BourgaultS.BasilleM.BurelD.WurtzO.et al (2009). Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery.Pharmacol. Rev.61283–357. 10.1124/pr.109.001370
106
WangM.YangY.WangC. J.GamoN. J.JinL. E.MazerJ. A.et al (2013). NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex.Neuron77736–749. 10.1016/j.neuron.2012.12.032
107
WellmanC. L. (2001). Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration.J. Neurobiol.49245–253. 10.1002/neu.1079
108
WellmanC. L.BollingerJ. L.MoenchK. M. (2020). Effects of stress on the structure and function of the medial prefrontal cortex: insights from animal models.Int. Rev. Neurobiol.150129–153. 10.1016/bs.irn.2019.11.007
109
YakaR.HeD. Y.PhamluongK.RonD. (2003). Pituitary adenylate cyclase-activating polypeptide (PACAP(1-38)) enhances N-methyl-D-aspartate receptor function and brain-derived neurotrophic factor expression via RACK1.J. Biol. Chem.2789630–9638. 10.1074/jbc.m209141200
110
YiuA. P.MercaldoV.YanC.RichardsB.RashidA. J.HsiangH. L.et al (2014). Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training.Neuron83722–735. 10.1016/j.neuron.2014.07.017
Summary
Keywords
PACAP, learning, working memory, fear, anxiety, cognition, sex, PTSD
Citation
Gilmartin MR and Ferrara NC (2021) Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory. Front. Cell. Neurosci. 15:663418. doi: 10.3389/fncel.2021.663418
Received
02 February 2021
Accepted
02 June 2021
Published
22 June 2021
Volume
15 - 2021
Edited by
Dora Reglodi, University of Pécs, Hungary
Reviewed by
Victor May, University of Vermont, United States; Seiji Shioda, Hoshi University, Japan; Hitoshi Hashimoto, Osaka University, Japan
Updates
Copyright
© 2021 Gilmartin and Ferrara.
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*Correspondence: Marieke R. Gilmartin, marieke.gilmartin@marquette.edu
This article was submitted to Cellular Neurophysiology, a section of the journal Frontiers in Cellular Neuroscience
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