Area of Research
Behavioural neuroscience, neurobiology, learning and memory, fear conditioning, systems consolidation, plasticity, epigenetics, histone variant exchange, chromatin, rodents
My research focuses on the neurobiological mechanisms through which transient experiences produce persistent behavioral outcomes. Memory formation is a primary example of a general phenomenon in behavioural science, whereby transient life experiences are transformed to produce long-lasting changes in the brain, and ultimately, in behaviour. Epigenetic mechanisms, which provide a bridge between environmental stimuli and gene regulation, have the potential to act as stable molecular marks required to support memory formation and maintenance over a lifetime.
Epigenetic modifications regulate access to DNA, which is obscured by its packaging into nucleosomes that consist of two each of histones H2A, H2B, H3, and H4. Nucleosome composition can be altered through the exchange of canonical histones with their replication-independent variants that differentially regulate DNA access and transcription. I recently demonstrated that histone H2A.Z, a variant of histone H2A, is actively exchanged during memory consolidation in both the hippocampus and the cortex, where it acts as a restraint on the formation of recent and remote memory. These findings introduce histone variant exchange as a novel epigenetic regulator of memory formation and transcription in the nervous system.
My interests center on elucidating the regulatory role of nucleosome composition and histone variant exchange in cognition, particularly in the context of co-occurring epigenetic modifications. Histone variants are an especially exciting target for memory stabilization because of our recent observation that cortical H2A.Z binding at memory-associated genes is altered long after the cessation of the learning event. Thus, studies aimed at uncovering the mechanisms through which histone exchange is regulated and in turn, how it regulates its downstream targets over time, can provide essential insights into the molecular basis of memory. To this end, my research focuses on multiple stages of memory formation, including initial and transient consolidation events in the hippocampus, as well as the gradual transfer of memories to the cortex in a process termed systems consolidation.
An important consideration in studies focused on any single modification is that epigenetic modifications do not occur in isolation and instead work together to regulate gene expression and, ultimately, behaviour. I am especially interested in understanding the coordinated effects of histone variants, post-translational modifications and DNA methylation in regulating memory formation and memory maintenance. These related lines of research converge on the broader issue of stimulus-induced plasticity in neural networks and their implications for establishing persistent behavioural outcomes.
Zovkic I & McCormick CM (2019) A rapid enhancement of locomotor sensitization to amphetamine by estradiol in female rats. Physiology and Behavior, 9384, 30405-30410.
Narkaj K*, Stefanelli G*, Azam AB*, Ramzan F*, Steininger CFD*, Walters BJ, Zovkic I (2018) Blocking H2A.Z incorporation via Tip60 inhibition promotes systems consolidation in mice. eNeuro, 5, 1-13.
Ramzan F*, Azam AB*, Monks A, Zovkic I (2018) Androgen receptor suppresses fear memory. Hormones & Behavior, 106, 10-18.
Kapadia M*, Mian F, Michalski B*, Azam A*, Ma D, Salwierz P, Christopher A*, Rosa E*, Zovkic I, Forsythe P, Fahnestock M, and Sakic B. (2018) Sex-dependent differences in spontaneous autoimmune manifestations in adult 3xTg-AD mice, Journal of Alzheimer’s Disease and Dementia, 63, 1191-1205
Faykoo Martinez M*, Monks DA, Zovkic I, Holmes MA. (2018) Sex- and brain region-specific patterns of gene expression associated with socially-mediated puberty in a eusocial mammal. Plos ONE, 13: e0193417
Stefanelli G*, Azam AB*, Walters BJ, Brimble MA*, Gettens CP*, Bouchard-Cannon P*, Cheng H-YM, Davidoff AM, Narkaj K, Day JJ, Kennedy JJ, & Zovkic I (2018) Learning and age-related changes in genome-wide H2A.Z binding in the mouse hippocampus. Cell Reports, 22, 1124-1131
Stefanelli G*, Walters BJ, Ramzan F*, Narkaj K*, Tao C*, & Zovkic I (2018) Epigenetic mechanisms of learning and memory. Handbook of Neurobehavioral Genetics, 345-382.
Walters BJ, Azam AB, Gillon CJ, Josselyn SA, Zovkic IB (2016) Advanced in-vivo use of CRISPR/Cas9 and anti-sense DNA inhibition for gene manipulation in the brain. Frontiers in Genetics, 6, 362-375.
Zovkic I & Sweatt, JD (2015) Memory-associated Dynamic Regulation of the “Stable” Core of the Chromatin Particle, Neuron, 87, 1-4.
Walters BJ & Zovkic I (2015) Building up and knocking down: An emerging role for epigenetics and proteasomal degradation in systems consolidation, Neuroscience, 300, 39-52. (Cover article)
Zovkic I & Walters BJ (2015) H2A.Z helps genes remember their history so we can remember ours. BioEssays, 37, 596-601.
Zovkic I, Paulukaitis B, Etikala D, Day JJ. & Sweatt, JD (2014) H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature, 515, 582-586.
Zovkic I, Meadows J & Sweatt JD (2013). Epigenetic mechanisms of PTSD. Frontiers in Psychiatry, 4, 60
Zovkic I, Guzman-Karlsson M & Sweatt JD (2013). Epigenetic regulation of memory formation and maintenance.
Learning & Memory, 20, 61-74. – Journal Cover
Zovkic I & Sweatt, JD (2013). Epigenetic mechanisms in learned fear: Implications for PTSD.
Neuropsychopharmacology, 38, 77-93
Mathews (Zovkic) I & McCormick CM (2012). Role of medial prefrontal dopamine in age differences in response to
amphetamine in rats: Locomotor activity after intra-mPFC injections of dopaminergic ligands. Developmental Neurobiology, 72, 1415-1421
McCormick CM, Thomas CM, Sheridan C, Nixon F, Flynn JA & Mathews (Zovkic) I (2011). Social instability stress in
adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in
adulthood. Hippocampus, 22, 1300-1312
Mathews (Zovkic) I, Brudzynski SM & McCormick CM (2011) Heightened locomotor-activating effects of
amphetamine administered into the nucleus accumbens in adolescent rats. International Journal of Developmental Neuroscience, 29, 501-507
Mathews (Zovkic) I, Kelly H & McCormick CM (2011). Low doses of amphetamine lead to immediate and lasting
locomotor sensitization in adolescent, not adult, male rats. Pharmacology, Biochemistry and Behavior, 97, 640-646
Morrisey MD, Mathews (Zovkic) I, & McCormick CM. (2010). Enduring deficits in contextual and auditory fear
conditioning after adolescent, not adult, social instability stress in male rats. Neurobiology of Learning &
Memory, 95, 46-56
Mathews (Zovkic) I, Morrissey MD, & McCormick CM (2010). Individual differences in activity predict locomotor
activity and conditioned place preference to amphetamine in both adolescent and adult rats. Pharmacology, Biochemistry, and Behaviour, 95, 63-71.
McCormick CM & Mathews (Zovkic) I. (2010). Adolescent development, hypothalamic-pituitary-adrenal function, and
programming of adult learning and memory. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34, 756-765.
McCormick CM, Mathews (Zovkic) I, Thomas C, & Waters PG (2010). Investigations of HPA function and the enduring
consequences of stressors in adolescence in animal models. Brain & Cognition, 72, 73-85.
Mathews (Zovkic) I, Waters PG & McCormick CM (2009). Changes in hyporesponsiveness to acute amphetamine and
age differences in tyrosine hydroxylase immunoreactivity in the brain over adolescence in male and female rats. Developmental Psychobiology, 51, 417-428.
Mathews (Zovkic) I, Wilton A, Styles A & McCormick CM (2008). Increased depressive behaviour in females and
heightened corticosterone release in males to swim stress after adolescent social stress in rats. Behavioural Brain Research, 190, 33-40.
Mathews (Zovkic) I, Mills R & McCormick CM (2008). Chronic social stress in adolescence influenced both
amphetamine conditioned place preference and locomotor sensitization. Developmental Psychobiology, 50, 451-459.
McCormick CM, Smith C & Mathews (Zovkic) I (2008). Effects of chronic social stress in adolescence on anxiety and
neuroendocrine response to mild stress in male and female rats. Behavioural Brain Research, 187, 228-238.
Mathews (Zovkic) I, & McCormick CM (2007). Female and male rats in late adolescence differ from adults in
amphetamine-induced locomotor activity, but not in conditioned place preference for amphetamine. Behavioural Pharmacology, 18, 641-50.
McCormick CM & Mathews (Zovkic) I (2007). HPA function in adolescence: Role of sex hormones in its regulation and
the enduring consequences of exposure to stressors. Pharmacology, Biochemistry, and Behavior, 86, 220-233.