Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats
Open accessAbstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in stress regulation and learning and memory. PACAP has neuromodulatory actions on brain structures within the limbic system that could contribute to its acute and persistent effects in animal models of stress and anxiety-like behavior. Here, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannula for infusion of PACAP-38 (0.5, 1, or 1.5 μg) or vehicle followed 30 min later by fear conditioning. Freezing was measured early (1, 4, and 7 days) or following a delay (7, 10, and 13 days) after conditioning. PACAP (1.5 μg) produced a bi-phasic response in freezing behavior across test days: relative to controls, PACAP-treated rats showed a reduction in freezing when tested 1 or 7 days after fear conditioning that evolved into a significant elevation in freezing by the third test session in the early, but not delayed, group. Corticosterone (CORT) levels were significantly elevated in PACAP-treated rats following fear conditioning, but not at the time of testing (Day 1). Brain c-Fos expression revealed PACAP-dependent alterations within, as well as outside of, areas typically implicated in fear conditioning. Our findings raise the possibility that PACAP disrupts fear memory consolidation by altering synaptic plasticity within neurocircuits normally responsible for encoding fear-related cues, producing a type of dissociation or peritraumatic amnesia often seen in people early after exposure to a traumatic event. However, fear memories are retained such that repeated testing and memory reactivation (e.g., re-experiencing) causes the freezing response to emerge and persist at elevated levels. PACAP systems may represent an axis on which stress and exposure to trauma converge to promote maladaptive behavioral responses characteristic of psychiatric illnesses such as post-traumatic stress disorder (PTSD).
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Treatment of dissociative identity disorder: leveraging neurobiology to optimize success
Purcell, J. B., Brand, B., Browne, H. A., Chefetz, R. A., Shanahan, M., Bair, Z. A., Baranowski, K. A., Davis, V., Mangones, P., Modell, R. L., et al. (2024) · Expert review of neurotherapeutics · doi:10.1080/14737175.2024.2316153 · Cited by 17 · see citing works
“Basic neuroscience studies of the neurotransmitter and neuromodulatory systems involved in distinct types of dissociative experiences would help elucidate future pharmacological targets for these experiences, and nascent attempts at this are underway [130,141].”
Background
- Authors
- Meloni, E. G., Venkataraman, A., Donahue, R. J., & Carlezon, W. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Meloni, Edward G.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 64
- Pages
- 12-21
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC4698186
- OpenAlex
- W2149315740
- Cited by
- 36
- References
- 64
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 4
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH097860, R56MH097860, R01MH097860)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- PACAP, pituitary adenylate cyclase-activating polypeptide, fear conditioning, fear memory consolidation, freezing behavior, Fos expression, corticosterone, stress, post-traumatic stress disorder, synaptic plasticity, limbic system, intracerebroventricular infusion
- MeSH terms
- Animals, Behavior, Animal, Brain, Conditioning, Psychological, Corticosterone, Dose-Response Relationship, Drug, Fear, Male, Time Factors, Proto-Oncogene Proteins c-fos, Freezing Reaction, Cataleptic, Pituitary Adenylate Cyclase-Activating Polypeptide, Rats, Infusions, Intraventricular
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