1.
Mechanisms underlying the effects of n-3 polyunsaturated fatty acids on fear memory processing and their hypothetical effects on fear of cancer recurrence in cancer survivors.
Okubo, R, Chen, C, Sekiguchi, M, Hamazaki, K, Matsuoka, YJ
Prostaglandins, leukotrienes, and essential fatty acids. 2018;:14-23
Abstract
The relationship of n-3 polyunsaturated fatty acids (PUFAs) and gut microbiota with brain function has been extensively reported. Here, we review how n-3 polyunsaturated fatty acids affect fear memory processing. n-3 PUFAs may improve dysfunctional fear memory processing via immunomodulation/anti-inflammation, increased BDNF, upregulated adult neurogenesis, modulated signal transduction, and microbiota-gut-brain axis normalization. We emphasize how n-3 PUFAs affect this axis and also focus on the hypothetical effects of PUFAs in fear of cancer recurrence (FCR), the primary psychological unmet need of cancer survivors. Its pathophysiology may be similar to that of post-traumatic stress disorder (PTSD), which involves dysfunctional fear memory processing. Due to fewer adverse effects than psychotropic drugs, nutritional interventions involving n-3 PUFAs should be acceptable for physically vulnerable cancer survivors. We are currently studying the relationship of FCR with n-3 PUFAs and gut microbiota in cancer survivors to provide them with a nutritional intervention that protects against FCR.
2.
Early-Life Adversity and Physical and Emotional Health Across the Lifespan: A Neuroimmune Network Hypothesis.
Nusslock, R, Miller, GE
Biological psychiatry. 2016;(1):23-32
-
-
Free full text
-
Abstract
Children who experience chronic stressors are vulnerable to emotional and physical health problems across the lifespan. This phenomenon raises questions for scientists and clinicians alike. How does adversity get under the skin of the developing child? Through what mechanisms does it confer vulnerability to a heterogeneous set of mental and physical illnesses? And how does it instantiate risk across different life stages, engendering vulnerability to conditions that develop shortly after stressor exposure-like depression-and conditions that manifest decades later, like heart disease? Although answers to these questions have started to emerge, research has typically focused on single diseases or organ systems. To understand the plethora of health problems associated with childhood adversity, we argue that the field needs a second generation of research that recognizes multidirectional transactions among biological systems. To help facilitate this process, we propose a neuroimmune network hypothesis as a heuristic framework for organizing knowledge from disparate literatures and as a springboard for generating integrative research. Drawing on existing data, we argue that early-life adversity amplifies crosstalk between peripheral inflammation and neural circuitries subserving threat-related, reward-related, and executive control-related processes. This crosstalk results in chronic low-grade inflammation, thereby contributing to adiposity, insulin resistance, and other predisease states. In the brain, inflammatory mediators act on cortico-amygdala threat and cortico-basal ganglia reward, circuitries in a manner that predisposes individuals to self-medicating behaviors like smoking, drug use, and consumption of high-fat diets. Acting in concert with inflammation, these behaviors accelerate the pathogenesis of emotional and physical health problems.
3.
HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?
Whittle, N, Singewald, N
Biochemical Society transactions. 2014;(2):569-81
-
-
Free full text
-
Abstract
A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy.