RESEARCH
For a list of funded grants and fellowships, click here.
For a list of recent seminars and conference presentations, click here.
What is mnemonic discrimination?
We rely heavily on our ability to form and retain detailed representations of similar experiences. Take, for example, the scenario of driving to work each morning.
Navigating the route from home is likely routine and a similar experience from day to day. However, to avoid evening frustration, it's adaptive to notice and remember the critical last detail of where you've parked your car.
Theoretical models propose this ability arises from pattern separation computations, assessed experimentally as mnemonic discrimination: distinguishing, from memory, between a previously seen target stimulus and similar lure stimuli.
The goal of my current research is to determine neurobiological mechanisms that contribute to mnemonic discrimination abilities across the lifespan, with a focus on how these mechanisms change in adulthood and aging. In rodent models, my approach combines longitudinal behavioral assessment, in vivo manipulation of neural activity, and circuit-specific mapping of neuronal population activity.
Rodent models to study mnemonic discrimination in aging
Mnemonic discrimination impairments are consistently observed in older adults and likely contribute to many symptoms of age-related memory loss.
To probe mechanisms underlying these impairments, my postdoc research centered on reverse translating (i.e. adapting from humans to rodents) tasks that assess mnemonic discrimination. I created a trial-based object discrimination task in which similarity of a rewarded target object (S+) to lure objects (S-) is parametrically varied.
I've demonstrated effects of lure similarity and aging on rodent task performance parallel effects of these factors in humans. Both young and aged rats perform well on easy trials with distinct lures, but poorly on difficult trials with similar lures. Critically, aged rats, relative to young adults, are impaired only in distinguishing similar lures, (Johnson et al. 2017; Maurer et al. 2017) and these impairments are more pronounced for object stimuli than spatial stimuli (Johnson et al. 2016).
Hippocampal and cortical contributions to mnemonic discrimination
Mnemonic discrimination impairments in aging are associated with altered activity in the lateral entorhinal cortex (EC), dentate gyrus (DG), and hippocampal CA3.
With the rodent task described above, we've demonstrated that transection of perforant path input from EC to the hippocampus recapitulates age-related deficits in mnemonic discrimination of similar stimuli (Burke et al. 2018). Disrupting neural activity within the dentate gyrus (DG) and CA3 also impairs mnemonic discrimination in young adult rats, though only when lure objects are novel (Johnson et al. 2018).
Most recently, we've found inactivation of prelimbic and infralimbic cortices impairs mnemonic discrimination irrespective of prior task experience, suggesting the frontal cortex modulates pattern separation functions by supporting working memory and reducing interference (Johnson et al. in prep).
To determine if aging impedes pattern separation functions of the hippocampus, as has been hypothesized from human data, recent studies mapped neuronal population coding of similar lures in young and aged rats. The population code across EC, CA3 and CA1 of young adult rats was consistent with intact pattern separation: overlapping populations of EC neurons – but divergent populations of HPC neurons – were active in distinguishing distinct versus similar lures. However, in aged rats, overlapping populations of neurons were active in EC, CA3, and CA1 during both distinct and similar lure discriminations, consistent with loss of pattern separation function (Johnson et al. in prep).
Novelty detection in hippocampal circuits
I currently hold a NIH Pathway to Independence award (K99/R00) to investigate processing of stimulus novelty by hippocampal circuits. Research on this grant is based on the working model that within the hippocampus, CA1 is a comparator of novel sensory input and existing memory representations. Release of catecholamines, particularly dopamine, and synaptic input from the locus coeruleus (LC) also converge in CA1, where they likely ramp up sensitivity to novelty. However, in aging, loss of catecholaminergic tone and LC structural integrity could predispose HPC circuits toward retrieval of existing representations, rather than encoding of novel inputs.
Ongoing experiments combine behavioral assessment in rodent touchscreen operant tasks, pharmacology, optogenetics, and circuit-specific mapping of neural activity to test this model and its implications for mnemonic discrimination impairments in aging.