The hippocampus has been implicated in anxiety disorders and post-traumatic stress disorder (PTSD); human studies suggest that a dysfunctional hippocampus may be a vulnerability factor for the development of PTSD. In the current study, we examined the effect of hippocampal damage in avoidance learning, as avoidance is a core symptom of all anxiety disorders. First, the effect of hippocampal damage on avoidance learning was investigated in outbred Sprague Dawley (SD) rats. Second, the function of the hippocampus in Wistar-Kyoto (WKY) rats was compared to SD rats. The WKY rat is an animal model of behavioral inhibition, a risk factor for anxiety, and demonstrates abnormal avoidance learning, marked by facilitated avoidance acquisition and resistance to extinction. The results of the current study indicate that hippocampal damage in SD rats leads to impaired extinction of avoidance learning similar to WKY rats. Furthermore, WKY rats have reduced hippocampal volume and impaired hippocampal synaptic plasticity as compared to SD rats. These results suggest that hippocampal dysfunction enhances the development of persistent avoidance responding and, thus, may confer vulnerability to the development of anxiety disorders and PTSD.
The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression has been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within thirty minutes when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated to the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within five minutes of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggests a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals.
Many questions have plagued the study of the etiology and subsequent treatment of mental illness. In part, it is simply because, as far as we know, some mental illnesses are somewhat unique to the human condition. Moreover, clinical studies have produced many different results concerning potential biomarkers for conditions such as post-traumatic stress disorder PTSD and major depressive disorder MDD . In this chapter, we review how we approached modeling a specific behavioral condition, suppression of the startle reflex, by examining whether one of two commonly associated peripheral biomarkers of anxiety and depression could potentially cause this rather specific symptom. The two peripheral systems under investigation were the hypothalamic-pituitary-adrenal HP" axis and the peripheral pro-inflammatory immune response, both of which have been implicated as a vulnerability factor, causal factor, or resultant perpetuating effect of PTSD and MDD.Our general theory is that peripheral endocrine and immune signals, measured to be abnormal in patients with either PTSD or MDD as well as other mental disorders , are actually perpetuating the behavioral features of these disorders. "t the same time, if an individual has an immunosensitivity or has an overactive adrenal gland, s/he would be more likely to experience some of the symptoms associated with one of the particular mental illnesses. This may then lead the brain to compensate for those peripheral abnormalities, but, at the same time, cause other imbalances, which lead to the experience of a decline into mental illness. Thus, treating these peripheral markers as part of the mental disorder may be quite beneficial in normalizing certain aspects of the diagnosed abnormal behavior.© 2013 Beck and Ca""zzi; licensee InTech. This is an open access ar"icle dis"rib""ed "nder "he "erms of "he Crea"ive Commons A""rib""ion License (h""p://crea"ivecommons.org/licenses/by/3.0), which permi"s "nres"ric"ed "se, dis"rib""ion, and reprod"c"ion in any medi"m, provided "he original work is properly ci"ed. . The startle reflex and mental health . . The startle reflex as an assessment toolOne of the major impediments to the mechanistic study of mental illness is establishing analogs of the abnormal behaviors expressed in humans in animal models, especially in sub-primate species. This has led some to adopt reflex-based measures such that the face and construct validity of the behavior change can be readily translated between the model and patient populations. Consequently, a popular measures for the study of anxiety disorders has been the potentiation of the startle reflex however, there is growing evidence that a dampening of the startle response may be indicative of changes in physiology that underlie different mental disorders.The startle reflex comprises a -synaptic sensory-motor neuronal pathway that serves as a defensive behavioral response to abrupt, usually intense, stimuli. The acoustic startle response "SR is the most commonly used form for studying this reflex. "s shown in Fig...
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