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Controlling the long-term impact of early life pain

Supervisors: Dr Simon Beggs, Professor Suellen Walker, Dr Paul Frankland and Dr Sheena Josselyn (University of Toronto)

Controlling the long-term impact of early life pain: cognitive dysfunction and the role of hippocampal neurogenesis

Background:
Preterm birth has a persistent impact on multiple health outcomes and with its increasing prevalence is a growing health care priority.  Exposure to repeated painful procedures and higher incidence of surgical interventions during neonatal intensive care, particularly after extreme pre-term birth (<28 weeks gestation), occurs at a time when the developing nervous system is vulnerable to altered levels of activity. It is becoming increasingly recognized that increased procedural pain exposure and neonatal surgery on brain structure and connectivity have a long-term impact with adverse neurodevelopmental outcome (Walker 2019). Early pain exposure has biological and psychosocial consequences.  This project will reveal the role of hippocampal function in the etiology of the cognitive dysfunction associated with early life injury.  Altered hippocampal circuitry biases and exaggerates adult pain experiences in patients with persistent pain but the role of early life changes in hippocampal structure and function is unclear.  Preliminary data from our animal models shows that pain in early life primes future pain responses (Moriarty et al 2019) and this is accompanied by a sex-dependent increase in hippocampal neurogenesis that is absent in adult animals with no prior pain experience. 

Hippocampal-dependent cognitive function may therefore be fundamentally altered at this critical stage with consequences that persist into later life (Chau et al 2019).

Aims/Objectives:
How does early life injury influence both the cognitive and physiological aspects of pain responses in later life? 

Aims:
1. To understand the neurobiological basis of the contribution of altered hippocampal neurogenesis to neurodevelopmental dysfunction and associated cognitive changes in later life. 
2. To identify and control the hippocampal neuronal ensembles that mediate early life injury-induced cognitive dysfunction and develop experimental strategies that both prevent and reverse them.

Methods:
We have developed a mouse model of neonatal surgical incision that leads to priming of adult pain responses (Moriarty et al 2019) and associated cognitive dysfunction (unpublished data).  A battery of standard established behavioural models will be used to quantify both nociceptive and cognitive function in mice with prior neonatal pain experience to fully categorize how adult cognition is affected by early life experience and also to document how it influences cognitive aspects of further pain experience in later life.

Preliminary experiments in our lab have shown that there are cellular and molecular changes, including altered neurogenesis, within the hippocampus, a structure associated with the cognitive dysfunction reported following early life injury.

In Toronto there will be the opportunity to use our established model of neonatal surgical incision with the Josselyn-Frankland lab’s in vivo retroviral and transgenic chemogenetic and optogenetic mouse models to manipulate hippocampal neuronal function.  These techniques will allow for the reversible activation and silencing of newborn neurons within the hippocampus of the adult animal and assess their impact on cognitive tasks.

Collaboration with University of Toronto:
In Toronto the successful student will work in the Josselyn-Frankland laboratory (https://jflab.ca/) and use their extensive array of in vivo models to assess the role of hippocampal neurogenesis in the long-term cognitive effects of early life injury.  In the first instance this will involve introducing our established model of early life incisional injury to the lab and using their molecular tools to manipulate hippocampal function and assessing its impact on injury-induced cognitive dysfunction. 

All relevant training requirements will be provided by the Josselyn-Frankland lab and Laboratory Animal Services at the Hospital for Sick Children.

The placement will be for an initial 6 months under the direct supervision of Drs Josselyn and Frankland and it is anticipated that their will be close collaboration for the extent of the PhD in order to establish appropriate models at ICH for further research for the duration on the PhD and beyond.

Timeline:
Using the mouse model of neonatal and adult incision allows strategies that are achievable within a PhD time scale. 

Year 1: characterization of cognitive dysfunction and hippocampal neurogenesis. 
Years 2 and 3: Initial 6 month placement in the Josselyn-Frankland lab in Toronto to learn the use of in vivo mouse models to manipulate hippocampal neuronal function.  It is anticipated the student will use the expertise learned during the visit to establish the techniques at ICH for the remainder of the PhD, in close alliance with Toronto colleagues.

References:
1.    Walker SM. Long-term effects of neonatal pain.  Semin Fetal Neonatal Med. 2019
2.    Chau et al. Hippocampus, Amygdala, and Thalamus Volumes in Very Preterm Children at 8 Years: Neonatal Pain and Genetic Variation.  Front Behav Neurosci 2019
3.    Moriarty et al. Priming of Adult Incision Response by Early-Life Injury.  J Neurosci 2019
4.    Akers et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy.  Science 2014
5.    Vetere et al. Memory formation in the absence of experience.  Nat Neurosci 2019.