Sustained Threat and Interval Timing

Arizona State University-Tempe Campus, Tempe AZ

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Threats and perceived danger typically activate defensive systems that, although adaptive, challenge physiological homeostasis in the nervous system. Sustained threats induce an allostatic load, resulting in sex- dependent aversive emotional states and compromised physiological, neural, and cognitive function, which may trigger and exacerbate various psychological disorders. Recent work has revealed that the brain structures recruited to estimate the passage of time (striatum, hippocampus, prefrontal cortex) are also implicated in a variety of psychological disorders, and are morphologically sensitive to chronic stress. A large amount of research supports a standard pacemaker-accumulator framework for computational and neurobiological theories of interval timing. This framework incorporates a range of motivational and cognitive processes that include working memory, long-term memory, decision-making, and arousal. Interval timing thus provides a unique window into potentially compromised cognitive processes in animal models. Surprisingly, there is a dearth of research on how chronic stress affects interval timing. This small project is a foundational effort at addressing this gap in the research literature. In particular, the proposed study will test the sensitivity of various components of the pacemaker-accumulator framework to CVS, and will preliminarily identify candidate neural correlates underlying this sensitivity. Adult male and female rats will be trained on one of two response-initiated interval-timing paradigms: a temporal production switch task (Experiment 1, prospective timing) and a temporal discrimination bisection task (Experiment 2, retrospective timing). The novel response- initiated feature of these tasks, along with a mixture-model analysis, will isolate stress-induced changes in timing from stress-induced changes in motivation. Once timing performance stabilizes, half of the rats in each group will undergo CVS and half will be minimally manipulated for 7 days, twice a day. Behavioral training will continue during CVS and control conditions. The effects of CVS on timing will be assessed by comparing pacemaker-accumulator parameters between CVS and control rats prior to, during, and after experimental conditions are implemented. Brains will be harvested at two time-points to assess training- and stress-induced changes in dendritic morphology in target regions. The correlation between morphological changes in target regions and changes in pacemaker-accumulator parameters across individual animals will provide preliminary clues of the regions involved in stress-induced timing effects. A subsequent R01 project will establish the causal link between these neural correlates and timing performance. In the long term, these outcomes may help characterize abnormal interval timing as either a symptom of various stress-related psychopathologies or as a core functional construct that underlies them. This key distinction would aid substantially in the development of novel treatments and diagnostic strategies.