Prefrontal cortex PACAP signaling: organization and role in stress regulation

Martelle, Susan E.; Cotella, Evelin M.; Nawreen, Nawshaba; Chen, Carrie; Packard, Benjamin A.; Fitzgerald, Malinda E.C.; Herman, James P.

doi:10.1080/10253890.2021.1887849

Cited by 13 publications

(6 citation statements)

References 41 publications

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“…PACAP plays a role in neuronal excitability (May et al 2021 ), urinary bladder activity (Girard et al 2021 ), gastrointestinal motility and secretion (Karpiesiuk and Palus 2021 ; Reglodi et al 2018 ; Rytel et al 2021 ), cartilage and bone formation (Jozsa et al 2021 ), and reproduction and embryonal growth (Koves et al 2020 ; Ross et al 2018 ; Shan et al 2021 ) and it also has immunomodulatory functions (Abad and Tan 2018 ). Several studies show that PACAP plays important roles in numerous pathological conditions such as tumor growth and proliferation (D’Amico et al 2021b , c ; Maugeri et al 2018a , 2021 ; Moody et al 2016 ) and nervous system disorders (Moody and Jensen 2021 ) like migraine, schizophrenia, anxiety, and depression (Eslami et al 2021 ; Kormos et al 2016 ; Martelle et al 2021 ; Ross et al 2020 ; Tiihonen et al 2021 ) as well as inflammatory conditions (Moody and Jensen 2021 ; Tamas et al 2021 ), sudden infant death syndrome (Shi et al 2021 ), and hearing loss (Fulop et al 2019 ; Ruel et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

et al. 2022

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Pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide with widespread distribution and diverse biological functions. Several studies show that PACAP has strong cytoprotective effects mediated mostly through its specific PAC1 receptor (PAC1-R) and it plays important roles in several pathological conditions. Its distribution and altered expression are known in various human tissues, but there is no descriptive data about PACAP and its receptors in the human eyebulb. Since PACAP38 is the dominant form of the naturally occurring PACAP, our aim was to investigate the distribution of PACAP38-like immunoreactivity in the human eye and to describe the presence of PAC1-R. Semiquantitative evaluation was performed after routine histology and immunohistochemical labeling on human eye sections. Our results showed high level of immunopositivity in the corneal epithelium and endothelium. Within the vascular layer, the iris and the ciliary body had strong immunopositivity for both PACAP and PAC1-R. Several layers of the retina showed immunoreactivity for PACAP and PAC1-R, but the ganglion cell layer had a special pattern in the immunolabeling. Labeling was observed in the neuropil within the optic nerve in both cases and glial cells displayed immunoreactivity for PAC1-R. In summary, our study indicates the widespread occurrence of PACAP and its specific receptor in the human eye, implying that the results from in vitro and animal studies have translational value and most probably are also present in the human eye.

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Section: Introductionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

et al. 2022

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“…In MDD, the main change was an increased mRNA expression of PACAP in the DLPFC. This shows that the human PFC has its own local PACAP system, with PACAP production and the presence of its receptors that have depression-related changes, as found for stress-related changes in rodents (Martelle et al, 2021).…”

Section: Discussionmentioning

confidence: 58%

Alterations in pituitary adenylate cyclase-activating polypeptide in major depressive disorder, bipolar disorder, and comorbid depression in Alzheimer's disease in the human hypothalamus and prefrontal cortex

Slabe,

Balesar,

Verwer

et al. 2023

Psychol. Med.

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Background Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders. Methods PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Results PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features. Conclusion The results support the possibility that PACAP plays a role in mood disorder pathophysiology.

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“…The amygdala-prefrontal circuit has been at the forefront of neurocircuitry models of PTSD for decades [ 15 , 16 , 83 – 85 ] and has been reliably implicated in the regulation of fear acquisition, expression, and extinction [ 86 – 88 ]. Evidence suggests PACAP is markedly expressed within prefrontal (infralimbic in rodents) structures, through which it may play a mechanistic role in fear learning and extinction [ 89 ]. However, prior human studies have similarly found no association between the PACAP-PAC1R system and prefrontal activity in relation to PTSD or threat reactivity [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating PACAP levels are associated with increased amygdala-default mode network resting-state connectivity in posttraumatic stress disorder

Clancy,

Devignes,

Kumar

et al. 2023

Neuropsychopharmacol.

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The pituitary adenylate cyclase-activating polypeptide (PACAP) system is implicated in posttraumatic stress disorder (PTSD) and related amygdala-mediated arousal and threat reactivity. PTSD is characterized by increased amygdala reactivity to threat and, more recently, aberrant intrinsic connectivity of the amygdala with large-scale resting state networks, specifically the default mode network (DMN). While the influence of PACAP on amygdala reactivity has been described, its association with intrinsic amygdala connectivity remains unknown. To fill this gap, we examined functional connectivity of resting-state functional magnetic resonance imaging (fMRI) in eighty-nine trauma-exposed adults (69 female) screened for PTSD symptoms to examine the association between blood-borne (circulating) PACAP levels and amygdala-DMN connectivity. Higher circulating PACAP levels were associated with increased amygdala connectivity with posterior DMN regions, including the posterior cingulate cortex/precuneus (PCC/Precun) and left angular gyrus (lANG). Consistent with prior work, this effect was seen in female, but not male, participants and the centromedial, but not basolateral, subregions of the amygdala. Clinical association analyses linked amygdala-PCC/Precun connectivity to anxious arousal symptoms, specifically exaggerated startle response. Taken together, our findings converge with previously demonstrated effects of PACAP on amygdala activity in PTSD-related processes and offer novel evidence for an association between PACAP and intrinsic amygdala connectivity patterns in PTSD. Moreover, these data provide preliminary evidence to motivate future work ascertaining the sex- and subregion-specificity of these effects. Such findings may enable novel mechanistic insights into neural circuit dysfunction in PTSD and how the PACAP system confers risk through a disruption of intrinsic resting-state network dynamics.

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Prefrontal cortex PACAP signaling: organization and role in stress regulation

Cited by 13 publications

References 41 publications

Distribution of PACAP and PAC1 Receptor in the Human Eye

Distribution of PACAP and PAC1 Receptor in the Human Eye

Alterations in pituitary adenylate cyclase-activating polypeptide in major depressive disorder, bipolar disorder, and comorbid depression in Alzheimer's disease in the human hypothalamus and prefrontal cortex

Circulating PACAP levels are associated with increased amygdala-default mode network resting-state connectivity in posttraumatic stress disorder

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