Professor, Undergraduate Chair
|Phone:||613-520-2600 x 1543|
|Office:||5307 Health Sciences Building|
Areas of Specialization / Field Affiliations
- Learning and memory, development, neurodegeneration, psychopharmacology, toxicology, concussions.
Eligible to supervise at the Graduate and Undergraduate level.
Current research in the Holahan Lab:
- The effects of low doses of phthalates on hippocampal development and plasticity.
- Preclinical models of Parkinson’s disease and development of novel treatment strategies.
- The role of the nucleus accumbens in rats with deficits in behavioral inhibition (operant extinction, operant training), possible model of addiction.
- The acquisition and expression of remote spatial memories during the juvenile period and how AMPA (glutamate receptor) blockade during development can effect spatial memories (Morris water maze task).
- In vivo and ex vivo models of concussion outcomes.
Current research Collaborators
- Natalina Salmaso (Neuroscience), Ken Storey (Biochemistry), Jeff Smith (Chemistry)
- Maria DeRosa (Chemistry)
- Francesco Leri (Guelph).
- Fernando Oliveira (UFABC, Brazil)
- Oren Petel (Engineering), Taryn Taylor (Sports Medicine), Cameron Marshall (Toronto).
Most Significant Contributions to Research and/or to Practical Applications
My contributions to research and highly qualified personnel training over the last six years have centered on the use of an integrative neuroscience approach to study influences on neural structure and function in the context of behavior. We examine the emergence of spatial information processing and long-term memory storage in rodents during development and associated axonal and dendritic changes that might subserve these functions. My students and I also use transgenic mouse models to investigate potential novel therapeutic targets in the treatment of Parkinson’s disease. We examine how environmental toxins and pharmacological manipulations influence brain function (immediate early gene expression, inflammatory markers) and structural connectivity. All of these lines have provided a fertile training ground for graduate and undergraduate students and fall under the domains of 1) development, 2) remote memory, 3) phthalate exposure, 4) aptamer use and 5) pharmacology.
This work provided 10 undergraduate students with honours’ projects (4 included as authors), has resulted in the following publications (Wartman, et al., 2012; Wartman, at al. 2012 (two papers, same year); Comba, et al. 2015; Tzakis, et al., 2016), forms the cornerstone of my NSERC and has contributed to the completion of 3 Master’s (all lead authors) and is being followed up by a current PhD and 2 MSc students. A past collaboration with Dave Mumby at Concordia University provided an excellent training environment for a number of graduate and undergraduate students contributing to this work. Students learned to work together to complete a large behavioral study at Concordia and coordinate brain extraction and transport to Carleton where students participated in immunohistochemical tissue processing. Not only were all students exposed to expertise provided by 2 researchers, but they also were exposed to the meshing and sharing of ideas generated to design a project and see it to publication. This work provided the foundation for an invited talk in Brazil and to the development of a research collaboration with a Brazilian investigator (Oliviera). This line of work has been influential in the way that developmental milestones are viewed with respect to memory processing and it has been utilized by the scientific community to explore the basic mechanisms that change during development as a way to manipulate these mechanisms and alter memory processing for the long-term.
- Remote memory
Three publications (Wartman and Holahan, 2013 & 2014; Wartman, et al, 2014) examined the factors, in addition to the passage of time, that can influence whether a memory enters into a systems consolidation process and comes to be stored in the cortex. A number of reports have shown that 30 days after a memory has been encoded, it comes to be stored in cortical areas such as the anterior cingulate cortex. This has been studied by exposing rodents to one task, allowing them to form a memory representation for the task then waiting different periods of time to determine, either through brain imaging or region-specific inactivation, the location of the memory representation. My PhD student (Brianne) examined this by training rats on sequential spatial tasks or spatial and nonspatial tasks to examine whether systems consolidation between the hippocampus and cortex can be modified by increasing information processing demand. In essence, she found that spatial memories come to rely more fully on cortical networks when hippocampal processing requirements are increased. She also found a continued involvement of the hippocampus in spatial memory retrieval along with a progressive strengthening of cortical connections as time progresses. This has had an impact on the direction of thinking about system consolidation processes in terms of what influences how and where a memory is ultimately stored in the brain. Other researchers have used similar sequential training manipulations to investigate other influences on memory dynamics. This work has allowed for a more comprehensive view of systems consolidation and improved ecological validity.
- Phthalate exposure
Our initial findings showed that phthalate treatment resulted in reduced axonal innervation, spine density and reduced indices of neurogenesis in the hippocampus in male, but not female, rats. These findings stimulated a search for why these effects were noted. With Smith in Chemistry, we found that phthalate treatment led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female, but not male, rats. These results suggested a neuroprotective effect of these elevated lipid species in females. This finding stimulated work with Storey in Biochemistry to explore microRNA expression after phthalate treatment. Results from this collaborative effort demonstrated that microRNA expression showed changes in females that supported a neuroprotective response mounted in females following phthalate exposure. Phthalate administration to male rats has been shown to negatively impact neural development while development of the female rat brain is less affected. Because a number of exogenous agents have been shown to interfere with dopamine function, we evaluated locomotor activity and tyrosine hydroxylase activity in both male and female rats. Stereological analysis revealed reduced TH+ densities in the substantia nigra in both phthalate-treated male and female rats. An examination of Th mRNA showed a main effect of sex with females showing increased Th expression at all phthalate doses. The scientific findings obtained using this model provide data indicating the various ways in which uncontrolled exposure to commercial toxins affect brain circuits. These data may help predict what could be potential dangers of similar exposure in humans and indicate why some populations show vulnerability to develop Parkinson’s disease.
- Aptamer use
Collaborative work with Maria DeRosa in Chemistry has explored the use of aptamers in the brain to quell neurodegenerative processes underlying Parkinson’s disease. The impact of developing an aptamer to serve as a “supplement” for impeding the toxic consequences of alpha-synuclein accumulation would be immense in terms of its value for both the study and treatment of Parkinson’s. The ability to inhibit protein aggregation with an exogenous treatment during aging would be a key strategy in studying and potentially slowing the neurodegenerative process. This work stems from two research papers (Holahan, et al., 2011; McConnell, Ventura, et al., 2018) and one review paper (McConnell, et al., 2014) and one paper under revision. This work has been supported by 3 years of funding from the Michael J. Fox Foundation and a current CIHR grant where we are designing aptamers to bind to alpha-synuclein and devising a strategy to deliver these aptamers across the blood brain barrier. This work has been instrumental for a PhD project and 2 MSc theses in Chemistry, a MSc project in Neuroscience (and continuing as PhD thesis in Neuroscience) and provided the mechanism for training of several undergraduate students in both Chemistry and Neuroscience. The impact of this project is also captured in our application for a provisional patent to cover the design and delivery of this alpha-synuclein binding aptamer as well as a collaboration with a pharmaceutical partner.
Under this research line, we have published 3 research papers (Holahan, et al., 2011; Davis-MacNevin, et al., 2013; Tuplin, et al., 2015) and one review paper (Tuplin and Holahan, 2017). This line of work has permeated my research program for several years and was instrumental as the focal point for a successful NSERC RTI application. Work on this line of research over the past 6 years has served as training for 2 MSc students (both continued on to PhD programs in Neuroscience), 2 summer NSERC students (one in medical school and the other in a Neuroscience PhD program) and 2 honour’s students who have also gone on to graduate programs in Neuroscience. This work has influenced the direction of thought for the current NSERC proposal in understanding the neurochemical modulation of early development and impact on both spatial and nonspatial information processing. Other users have been able to glean dose-response information from these studies and potential interactions between drugs on behavioral and neural endpoints.
NSERC Discovery Grant
The objectives are to determine how juvenile memories are consolidated in the long-term with respect to 1) their dependence on AMPA receptor activation thereby investigating the initial stages of cellular consolidation, 2) whether juvenile-processed memories will progress through systems consolidation similar to that seen in adult rodents, 3) how these remotely stored, juvenile memories will affect the consolidation of adult-formed memories and 4) whether over time, these memories come back to rely on the neural locus (e.g., the hippocampus) that was responsible for the initial cellular consolidation processes, forming a loop in systems consolidation (hippocampus to cortex and back to hippocampus).
Related to the NSERC grant, we are currently investigating chronic exposure to phthalates during critical developmental periods and the alteration of the plastic properties of brain circuits associated with memory. Postnatal exposure to phthalates during a brain growth spurt in rodents has been shown to alter levels of proteins involved in brain maturation. Examination of cognitive function following early post-natal phthalate exposure revealed learning and memory deficits on the Morris water maze test. What is not known is what happens in the long-term after a developing organism (a 20 day-old rat) has been exposed to chronic, low-levels of phthalates during sensitive developmental periods.
Preclinical Animal Models of Schizophrenia
One research initiative that has gained steam over the last 5 years consists of investigating the pharmacological aspects underlying perseverative behavior. The primary purpose of this research program is to investigate the neurobiological mechanisms that underlie the processing of appetitive environmental events. A major theme is to study the development, persistence and termination of appetitively-motivated behaviour at the synaptic and systems levels in the brain and the contribution of dopamine.
Collaborative work with Maria DeRosa funded by the Michael J. Fox foundation is examining the use of aptamers to bind to alpha-synuclein and devising a strategy to deliver these aptamers across the blood brain barrier. A body of evidence suggests that aggregation of the neuronal protein, alpha-synuclein, plays a critical role in the neurodegenerative processes underlying Parkinson’s disease. Neurodegeneration associated with this disease is hypothesized to be caused by an accumulation in the intracellular concentration of either the native or mutant alpha-synuclein protein, leading to aggregation of the protein into inclusions (aggresomes) that can trigger apoptotic signals. With this premise, our current work asks the question: Can a DNA aptamer targeted to bind to alpha-synuclein and inhibit protein aggregation and reduce Parkinson’s–related neurodegeneration?
Another research undertaking has been to work with the athletics unit at Carleton and assess athletes prior to and following (up to 3 months) a concussion. This work has been largely spear-headed by a Master’s student in conjunction with Dr. Hymie Anisman’s lab. Although the majority of post concussive symptoms, including headaches, memory deficits or frustration, arrest after a few days or weeks, some athletes have prolonged symptoms. The reasoning behind this is not completely understood, but has been proposed to be indirectly attributed to the ability to cope with stressors. Considering that the outcomes of concussions can be severe, it is necessary that the signs, symptoms, and vulnerabilities be clearly understood in order to increase the rate of detection and predict individuals that may be at an increased risk for long-term deficits following a concussion.