Andrew M. Poulos - US grants

DESCRIPTION (provided by applicant): Trauma during early childhood is a major risk factor for the adult development of anxiety disorders such as post-traumatic stress disorder (PTSD). Determining the underlying causes of this relationship has remained extraordinarily challenging. In particular, determining how the functional state of the brain at the time of trauma contributes to PTSD and its neural underpinnings remains an elusive goal. Prior efforts, using animal models have mainly focused on maternal-separation procedures as early life stressors. We propose the use of painful foot shocks as a trauma procedure given that it is a major component of child abuse. This procedure when presented at different post-natal ages has yielded important insights into the ontogeny of fear learning. Our laboratory has substantial experience in adult fear conditioning, with the above procedure in the mature animal resulting in a life-long memory of the trauma that depends on the amygdala (AMY), hippocampus (HIPP) and prefrontal cortex (PFC). Importantly, if this fear experience is strong enough it results in a sustained vulnerability to over-exaggerate fear responses even to mild reminders of the original trauma. This sensitized fear response is a central characteristic of PTSD. Our approach identifies 3 key hypotheses based on the timing of early life trauma (figure A): 1) Early Post-natal trauma during Stage 1: Prior to the functional maturation of AMY, fear learning systems cannot be sufficiently activated. 2) Middle Post-natal trauma during Stage 2: After the functional maturation of the AMY, but prior to the maturation of hippocampal context processing pathways, associative fear responses cannot be established, yet non-associative sensitization of fear and neuroendocrine responses persist. 3) Late Post-natal trauma during Stage 3: With the maturation of both systems both appropriate conditional responses can be acquired as well as a sustained adult enhancement of amygdala-based fear learning. To test these hypothesize we propose to identify the functional status of the fear neural circuits to early life trauma and how this contributes to development of adult PTSD related symptomology. This will be accomplished by using a neuroanatomical approach in which we are capable of characterizing the expression of immediately early genes within the amygdala and its associated afferent and efferent brain regions in response to repeated footshock trauma during early (P8), middle (P19) and late (P35) post-natal development. Next we address the long-lasting impact of trauma at these developmental time points on adult fear and neuroendocrine function. By understanding the how the maturing brain is susceptible to early-life trauma, this could provide great insight into mechanisms underlying a debilitating anxiety disorders such as PTSD.

Understanding the post-natal emergence and progression of episodic/hippocampal based and affective/amygdala based learning and memory systems in male and female animals can lead to significant advances in education, anxiety disoders and a detailed understanding of neural basis of learning and memory. We start off with the basic observation that learning and memory in children and young animals are particulary distinct when compared to adult mammalian counterparts. Our central hypothesis is that early in development, affective neural circuits dominate learning and that later, cognitive neural circuits emerge to further regulate learned behaviors. Moreover, the development and function of each these memory systems are influenced by perinatal gonadal hormones, resulting in sex differentiation of learning and memory. This hypothesis is grounded in the knowledge that late maturing hippocampal and prefrontal cortical circuits are fine-tuned to encode patterns of contextual-spatial elements and at test are capable to sufficiently retrieve this same pattern of elements.This pattern completion view of perceptual learning is combined with the knowledge that the basolateral and central amygdala microcircuits emerge earlier in development and are crucial for emotional learning including fear. We approach these questions by using standard and modified Contextual Fear Conditioning procedures in combination with neuroanatomical tools to create whole-brain functional neural acitivity maps underlying learning and memory across developmental lifespan of the male and female rat. These data will be used to create an open access database of all raw data, functional maps and group analytics. In addition, these data will be used to target inactivation of key neural pathways in the acquisition, retention and retriveal of contextual fear memories.