The neuropeptide slow transmitter PACAP (pituitary adenylate cyclase activating polypeptide) is released at synapses that transduce stress responses to the brain, and mediate homeostatic adjustments to stress by the organism. Allostatic responses to systemic and psychogenic stressors at multiple points in development and throughout the life span are implicated as a causative factor in depression and post-traumatic stress disorder (PTSD). Stress response pathways (resilience responses) may also be required to ameliorate delayed neuronal death (DND) in trauamtic brain injury, long-term exposure to intense physical or psychological stimuli, or brain inflammation in chronic neurodegenerative disease. Understanding the cellular mechanisms of stress transduction is crucial to developing effective therapeutic interventions for these disorders. We have previously shown that PACAP released at the adrenomedullary synapse is required for prolonged catecholamine release that promotes glucohomeostasis, and survival, during prolonged metabolic (hypoglycemic) stress. In the past year, we have found that PACAP's actions at this synapse include not only enhanced catecholamine synthesis and release, but increased transcription of genes encoding neuroprotective and steroidogenic factors (N. Stroth, B. Kuri, D. Ait-Ali, M. Gerdin, Y. Holighaus, C. Smith and L. Eiden, in preparation, 2010a;N. Stroth and L. Eiden, in preparation, 2010b). These presumably limit cellular damage accompanying overstimulation of stress-transducing cells, and augment production of adrenocortical steroids that mediate long-term adaptation to stress. PACAP contained in and released from neurons in the hypothalamus of the brain is also important in the central nervous system response to psychological stress. Hypothalamic responses leading to pituitary and adrenocortical activation following exposure to at least one type of psychogenic stressor (restraint stress) is significantly blunted in PACAP-deficient mice (N. Stroth and L. Eiden, Neuroscience 165:1025, 2010). PACAP activates several genes in cultured bovine chromaffin cells which are also regulated by PACAP during stress in vivo, including those encoding steroidogenic and neuroprotective secreted peptides, such as galanin, stanniocalcin, and VIP. This induction is dependent on a novel cAMP-dependent, PKA-independent signaling pathway different from the one required for cAMP- and calcium-dependent effects on memory and learning. We have now characterized this signaling pathway so that pharmacological interventions in stress relevant to mental health might be developed that do not at the same time interfere with normal processes of memory and learning that depend on cyclic AMP. We have also characterized the induction of the neuro- and cardio-protective gene product stanniocalcin as a PACAP-regulated gene in cultured rat cortical neurons, and demonstrated that this pathway is also a cAMP-dependent, PKA-independent one (Y. Holighaus, T. Mustafa, and L. Eiden, 418.6/C33, 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online). In a project initiated in 2009, we and our colleagues at the University of Gronigen in the Netherlands have continued to study the role of TNF-alpha in neuroprotection and inflammation in the brain. We have obtained confirmation, using cultured cortical neurons from TNFR1 and TNFR2 knock-out mice, that gene induction through the TNFR1 and TNFR2 receptors mediates induction of cytotoxic and cytoprotectant factors potentially mediating cell death and neuroresilience, respectively, under conditions of chronic brain inflammation. We have obtained initial expeerimental support for the hypothesis that at least one novel gene induced via type 1 TNF receptor elevation is a secreted polypeptide that is deleterious to neuronal survival through enhancement of A-beta-induced cytotoxicity. The protein product of this gene will be measured in cerebrospinal fluid of Alzheimer's disease patients as a potential biomarker for the progression of this disease in the coming months. A related recent finding obtained in collaboration with investigators at Philipps University, Marburg Germany is that cyclooxygenase 1 is specifically expressed in cholinergic neurons during chronic viral infection of the primate brain, and is down-regulated by SIV during the course of neuro-AIDS in an antiretroviral treatment-resistant fashion (C. Depboylu, E. Weihe, and L. Eiden, in preparation, 2010). The identification of secreted factors and the enzymes responsible for their biosynthesis in chronic neurodegenerative and inflammatory brain disease is anticipated to be relevant to the development of pharmacological agents to ameliorate inflammation-associated chronic neurodegenerative processes affecting cognition in the elderly, and cognitive decline associated with chronic lentivirus infection of the brain.
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